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1.
BMC Cancer ; 24(1): 319, 2024 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-38454443

RESUMEN

BACKGROUND: A high expression pattern of minichromosome maintenance 2 (MCM2) has been observed in various cancers. MCM2 is a protein involved in the cell cycle and plays a role in cancer growth and differentiation by binding to six members of the MCM subfamily. The MCM protein family includes MCM2 through MCM7. METHODS: MCM2 has shown high expression in both lung cancer stem cells (LCSCs) and glioma stem cells (GSCs). We investigated the characteristics of CSCs and the regulation of the epithelial-to-mesenchymal transition (EMT) phenomenon in LCSCs and GSCs by MCM2. Additionally, we explored secreted factors regulated by MCM2. RESULTS: There was a significant difference in survival rates between lung cancer patients and brain cancer patients based on MCM2 expression. MCM2 was found to regulate both markers and regulatory proteins in LCSCs. Moreover, MCM2 is thought to be involved in cancer metastasis by regulating cell migration and invasion, not limited to lung cancer but also identified in glioma. Among chemokines, chemokine (C-X-C motif) ligand 1 (CXCL1) was found to be regulated by MCM2. CONCLUSIONS: MCM2 not only participates in the cell cycle but also affects cancer cell growth by regulating the external microenvironment to create a favorable environment for cells. MCM2 is highly expressed in malignant carcinomas, including CSCs, and contributes to the malignancy of various cancers. Therefore, MCM2 may represent a crucial target for cancer therapeutics.


Asunto(s)
Neoplasias Pulmonares , Proteínas de Mantenimiento de Minicromosoma , Humanos , Quimiocina CXCL1 , Proteínas de Mantenimiento de Minicromosoma/genética , Proteínas , Células Madre Neoplásicas/metabolismo , Componente 2 del Complejo de Mantenimiento de Minicromosoma/genética , Componente 2 del Complejo de Mantenimiento de Minicromosoma/metabolismo , Proteínas de Ciclo Celular/genética , Microambiente Tumoral
2.
Biochem Biophys Res Commun ; 682: 141-147, 2023 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-37806253

RESUMEN

Baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5) is also known as survivin. BIRC5, a member of the apoptosis inhibitor (IAP) family, negatively regulates apoptosis or programmed cell death by inhibiting caspase activation. Due to these properties, overexpression of BIRC5 enables specific survival and division associated with cancer malignancies. In addition, BIRC5 is highly expressed in stem cells, but not present at all in terminally differentiated cells. On this basis, there is speculation that BIRC5 may be involved in the regulation of cancer stem cells (CSCs), but few study results have been reported. In addition, the molecular mechanisms of BIRC5 regulation are not yet well understood. Through the present study, it was confirmed that BIRC5 is a key factor regulating CSCs and epithelial to mesenchymal transition (EMT). BIRC5 was simultaneously overexpressed in lung cancer stem cells (LCSCs) and glioma stem cells (GSCs), and when the expression was suppressed, the characteristics of CSCs disappeared. In addition, plasminogen activator inhibitor-1 (PAI-1), a secreted factor regulated by BIRC5, is involved in signaling mechanisms that regulate cancer stem cells and EMT, and PAI-1 forms an autocrine chain. Based on these results, BIRC5 is proposed as a novel therapeutic target protein for LCSCs and GSCs.


Asunto(s)
Neoplasias Pulmonares , Inhibidor 1 de Activador Plasminogénico , Humanos , Transición Epitelial-Mesenquimal , Neoplasias Pulmonares/genética , Células Madre Neoplásicas , Pulmón , Survivin/genética
3.
Mar Drugs ; 21(12)2023 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-38132928

RESUMEN

The discovery of new highly effective anticancer drugs with few side effects is a challenge for drug development research. Natural or synthetic anticancer peptides (ACPs) represent a new generation of anticancer agents with high selectivity and specificity. The rapid emergence of chemoradiation-resistant lung cancer has necessitated the discovery of novel anticancer agents as alternatives to conventional therapeutics. In this study, we synthesized a peptide containing 22 amino acids and characterized it as a novel ACP (MP06) derived from green sea algae, Bryopsis plumosa. Using the ACP database, MP06 was predicted to possess an alpha-helical secondary structure and functionality. The anti-proliferative and apoptotic effects of the MP06, determined using the cytotoxicity assay and Annexin V/propidium iodide staining kit, were significantly higher in non-small-cell lung cancer (NSCLC) cells than in non-cancerous lung cells. We confirmed that MP06 suppressed cellular migration and invasion and inhibited the expression of N-cadherin and vimentin, the markers of epithelial-mesenchymal transition. Moreover, MP06 effectively reduced the metastasis of tumor xenografts in zebrafish embryos. In conclusion, we suggest considering MP06 as a novel candidate for the development of new anticancer drugs functioning via the ERK signaling pathway.


Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Animales , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Pez Cebra , Línea Celular Tumoral , Movimiento Celular , Transición Epitelial-Mesenquimal , Proliferación Celular , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico
4.
Int J Mol Sci ; 24(7)2023 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-37047826

RESUMEN

Cancer stem cells (CSCs) are known to be one of the factors that make cancer treatment difficult. Many researchers are thus conducting research to efficiently destroy CSCs. Therefore, we sought to suggest a new target that can efficiently suppress CSCs. In this study, we observed a high expression of Ran-binding protein 1 (RanBP1) in lung cancer stem cells (LCSCs) and glioma stem cells (GSCs). Upregulated RanBP1 expression is strongly associated with the expression of CSC marker proteins and CSC regulators. In addition, an elevated RanBP1 expression is strongly associated with a poor patient prognosis. CSCs have the ability to resist radiation, and RanBP1 regulates this ability. RanBP1 also affects the metastasis-associated epithelial-mesenchymal transition (EMT) phenomenon. EMT marker proteins and regulatory proteins are affected by RanBP1 expression, and cell motility was regulated according to RanBP1 expression. The cancer microenvironment influences cancer growth, metastasis, and cancer treatment. RanBP1 can modulate the cancer microenvironment by regulating the cytokine IL-18. Secreted IL-18 acts on cancer cells and promotes cancer malignancy. Our results reveal, for the first time, that RanBP1 is an important regulator in LCSCs and GSCs, suggesting that it holds potential for use as a potential therapeutic target.


Asunto(s)
Glioma , Neoplasias Pulmonares , Humanos , Interleucina-18/metabolismo , Línea Celular Tumoral , Neoplasias Pulmonares/metabolismo , Transición Epitelial-Mesenquimal , Células Madre Neoplásicas/metabolismo , Glioma/metabolismo , Microambiente Tumoral
5.
Molecules ; 27(24)2022 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-36557987

RESUMEN

Glioblastoma multiforme (GBM) is a fast-growing and aggressive type of brain cancer. Unlike normal brain cells, GBM cells exhibit epithelial-mesenchymal transition (EMT), which is a crucial biological process in embryonic development and cell metastasis, and are highly invasive. Copper reportedly plays a critical role in the progression of a variety of cancers, including brain, breast, and lung cancers. However, excessive copper is toxic to cells. D-penicillamine (DPA) and triethylenetetramine (TETA) are well-known copper chelators and are the mainstay of treatment for copper-associated diseases. Following treatment with copper sulfate and DPA, GBM cells showed inhibition of proliferation and suppression of EMT properties, including reduced expression levels of N-cadherin, E-cadherin, and Zeb, which are cell markers associated with EMT. In contrast, treatment with copper sulfate and TETA yielded the opposite effects in GBM. Genes, including TGF-ß, are associated with an increase in copper levels, implying their role in EMT. To analyze the invasion and spread of GBM, we used zebrafish embryos xenografted with the GBM cell line U87. The invasion of GBM cells into zebrafish embryos was markedly inhibited by copper treatment with DPA. Our findings suggest that treatment with copper and DPA inhibits proliferation and EMT through a mechanism involving TGF-ß/Smad signaling in GBM. Therefore, DPA, but not TETA, could be used as adjuvant therapy for GBM with high copper concentrations.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Animales , Glioblastoma/metabolismo , Cobre/farmacología , Pez Cebra , Línea Celular Tumoral , Sulfato de Cobre/farmacología , Neoplasias Encefálicas/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/farmacología , Quelantes/farmacología , Transición Epitelial-Mesenquimal , Movimiento Celular
6.
Int J Mol Sci ; 21(18)2020 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-32971893

RESUMEN

Studies have shown that cancer stem cells (CSCs) are involved in resistance and metastasis of cancer; thus, therapies targeting CSCs have been proposed. Here, we report that heat shock 70-kDa protein 1-like (HSPA1L) is partly involved in enhancing epithelial-mesenchymal transition (EMT) and CSC-like properties in non-small cell lung cancer (NSCLC) cells. Aldehyde dehydrogenase 1 (ALDH1) is considered a CSC marker in some lung cancers. Here, we analyzed transcriptional changes in genes between ALDH1high and ALDH1low cells sorted from A549 NSCLC cells and found that HSPA1L was highly expressed in ALDH1high cells. HSPA1L played two important roles in enhancing CSC-like properties. First, HSPA1L interacts directly with IGF1Rß and integrin αV to form a triple complex that is involved in IGF1Rß activation. HSPA1L/integrin αV complex-associated IGF1Rß activation intensified the EMT-associated cancer stemness and γ-radiation resistance through its downstream AKT/NF-κB or AKT/GSK3ß/ß-catenin activation pathway. Secondly, HSPA1L was also present in the nucleus and could bind directly to the promoter region of ß-catenin to function as a transcription activator of ß-catenin, an important signaling protein characterizing CSCs by regulating ALDH1 expression. HSPA1L may be a novel potential target for cancer treatment because it both enhances IGF1Rß activation and regulates γß-catenin transcription, accumulating CSC-like properties.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/metabolismo , Células Madre Neoplásicas/metabolismo , Receptor IGF Tipo 1/metabolismo , Transcripción Genética , beta Catenina/biosíntesis , Células A549 , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas HSP70 de Choque Térmico/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/patología , Receptor IGF Tipo 1/genética , beta Catenina/genética
7.
Stem Cells ; 35(9): 2037-2049, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28543863

RESUMEN

Basic fibroblast growth factor (bFGF) supplementation is critical to maintain the pluripotency of human pluripotent stem cells (hPSCs) through activation of PI3K/AKT, rather than MEK/ERK pathway. Thus, elaborate molecular mechanisms that preserve PI3K/AKT signaling upon bFGF stimulation may exist in hPSCs. Protein arginine methyltransferase 8 (PRMT8) was expressed and then its level gradually decreased during spontaneous differentiation of human embryonic stem cells (hESCs). PRMT8 loss- or gain-of-function studies demonstrated that PRMT8 contributed to longer maintenance of hESC pluripotency, even under bFGF-deprived conditions. Direct interaction of membrane-localized PRMT8 with p85, a regulatory subunit of PI3K, was associated with accumulation of phosphoinositol 3-phosphate and consequently high AKT activity. Furthermore, the SOX2 induction, which was controlled by the PRMT8/PI3K/AKT axis, was linked to mesodermal lineage differentiation. Thus, we propose that PRMT8 in hESCs plays an important role not only in maintaining pluripotency but also in controlling mesodermal differentiation through bFGF signaling toward the PI3K/AKT/SOX2 axis. Stem Cells 2017;35:2037-2049.


Asunto(s)
Linaje de la Célula , Células Madre Embrionarias Humanas/metabolismo , Proteínas de la Membrana/metabolismo , Mesodermo/citología , Fosfatidilinositol 3-Quinasas/metabolismo , Células Madre Pluripotentes/citología , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factores de Transcripción SOXB1/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Linaje de la Célula/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Factor 2 de Crecimiento de Fibroblastos/farmacología , Células Madre Embrionarias Humanas/citología , Células Madre Embrionarias Humanas/efectos de los fármacos , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Biológicos , Fenotipo , Células Madre Pluripotentes/efectos de los fármacos , Células Madre Pluripotentes/metabolismo , Unión Proteica/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
8.
Cancer Sci ; 106(6): 718-725, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25854938

RESUMEN

Metastasis of breast cancer is promoted by epithelial-mesenchymal transition (EMT). Emerging evidence suggests that STAT3 is a critical signaling node in EMT and is constitutively activated in many carcinomas, including breast cancer. However, its signaling mechanisms underlying persistent activation of STAT3 associated with EMT remain obscure. Here, we report that PIM2 promotes activation of STAT3 through induction of cytokines. Activation of STAT3 caused an increase in PIM2 expression, implicating a positive feedback loop between PIM2 and STAT3. In agreement, targeting of either PIM2, STAT3 or PIM2-dependent cytokines suppressed EMT-associated migratory and invasive properties through inhibition of ZEB1. Taken together, our findings identify the signaling mechanisms underlying the persistent activation of STAT3 and the oncogenic role of PIM2 in EMT in breast cancer.


Asunto(s)
Neoplasias de la Mama/patología , Transición Epitelial-Mesenquimal , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Proto-Oncogénicas/fisiología , Factor de Transcripción STAT3/fisiología , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Movimiento Celular , Femenino , Proteínas de Homeodominio/fisiología , Humanos , Interleucina-1alfa/metabolismo , Interleucina-8/metabolismo , Invasividad Neoplásica , Transducción de Señal , Factores de Transcripción/fisiología , Homeobox 1 de Unión a la E-Box con Dedos de Zinc
9.
Cancer Sci ; 106(1): 78-85, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25533622

RESUMEN

Despite the fact that ionizing radiation (IR) is widely used as a standard treatment for breast cancer, much evidence suggests that IR paradoxically promotes cancer malignancy. However, the molecular mechanisms underlying radiation-induced cancer progression remain obscure. Here, we report that irradiation activates SRC signaling among SRC family kinase proteins, thereby promoting malignant phenotypes such as invasiveness, expansion of the cancer stem-like cell population, and resistance to anticancer agents in breast cancer cells. Importantly, radiation-activated SRC induced SLUG expression and caused epithelial-mesenchymal cell transition through phosphatidylinositol 3-kinase/protein kinase B and p38 MAPK signaling. In agreement, either inhibition of SRC or downstream signaling of p38 MAPK or protein kinase B effectively attenuated radiation-induced epithelial-mesenchymal cell transition along with an increase in the cancer stem-like cell population. In addition, downregulation of SRC also abolished radiation-acquired resistance of breast cancer cells to anticancer agents such as cisplatin, etoposide, paclitaxel, and IR. Taken together, our findings suggest that combining radiotherapy with targeting of SRC might attenuate the harmful effects of radiation and enhance the efficacy of breast cancer treatment.


Asunto(s)
Familia-src Quinasas/metabolismo , Neoplasias de la Mama , Movimiento Celular/efectos de la radiación , Resistencia a Antineoplásicos/efectos de la radiación , Activación Enzimática , Transición Epitelial-Mesenquimal/efectos de la radiación , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Sistema de Señalización de MAP Quinasas , Células MCF-7 , Células Madre Neoplásicas/metabolismo , Fenotipo , Fosfatidilinositol 3-Quinasas/metabolismo , Factores de Transcripción de la Familia Snail , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
10.
Cancer Sci ; 106(1): 94-101, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25456733

RESUMEN

Metastasis is a challenging clinical problem and the primary cause of death in breast cancer patients. However, there is no therapeutic agent against metastasis of breast cancer cells. Here we report that phloroglucinol, a natural phlorotannin component of brown algae suppresses metastatic ability of breast cancer cells. Treatment with phloroglucinol effectively inhibited mesenchymal phenotypes of basal type breast cancer cells through downregulation of SLUG without causing a cytotoxic effect. Importantly, phloroglucinol decreased SLUG through inhibition of PI3K/AKT and RAS/RAF-1/ERK signaling. In agreement with in vitro data, phloroglucinol was also effective against in vivo metastasis of breast cancer cells, drastically suppressing their metastatic ability to lungs, and extending the survival time of mice. Collectively, our findings demonstrate a novel anticancer activity of phloroglucinol against metastasis of breast cancer cells, implicating its clinical relevance.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Floroglucinol/farmacología , Animales , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/patología , Movimiento Celular , Femenino , Humanos , Neoplasias Pulmonares/secundario , Sistema de Señalización de MAP Quinasas , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Floroglucinol/uso terapéutico , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Toxicol Appl Pharmacol ; 286(3): 143-50, 2015 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-25843036

RESUMEN

Poor prognosis of breast cancer patients is closely associated with metastasis and relapse. There is substantial evidence supporting that cancer stem-like cells (CSCs) are primarily responsible for relapse in breast cancer after anticancer treatment. However, there is a lack of suitable drugs that target breast cancer stem-like cells (BCSCs). Here, we report that phloroglucinol (PG), a natural phlorotannin component of brown algae, suppresses sphere formation, anchorage-independent colony formation and in vivo tumorigenicity. In line with these observations, treatment with PG also decreased CD44(+) cancer cell population as well as expression of CSC regulators such as Sox2, CD44, Oct4, Notch2 and ß-catenin. Also, treatment with PG sensitized breast cancer cells to anticancer drugs such as cisplatin, etoposide, and taxol as well as to ionizing radiation. Importantly, PG inhibited KRAS and its downstream PI3K/AKT and RAF-1/ERK signaling pathways that regulate the maintenance of CSCs. Taken together, our findings implicate PG as a good candidate to target BCSCs and to prevent the disease relapse.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Floroglucinol/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células Madre Neoplásicas/patología , Floroglucinol/química , Floroglucinol/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
12.
J Biol Chem ; 287(23): 19516-27, 2012 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-22511756

RESUMEN

The prognosis of breast cancer patients is related to the degree of metastasis. However, the mechanisms by which epithelial tumor cells escape from the primary tumor and colonize at a distant site are not entirely understood. Here, we analyzed expression levels of pituitary tumor-transforming gene-1 (PTTG1), a relatively uncharacterized oncoprotein, in patient-derived breast cancer tissues with corresponding normal breast tissues. We found that PTTG1 is highly expressed in breast cancer patients, compared with normal tissues. Also, PTTG1 expression levels were correlated with the degree of malignancy in breast cancer cell lines; the more migratory and invasive cancer cell lines MDA-MB-231 and BT549 displayed the higher expression levels of PTTG1 than the less migratory and invasive MCF7 and SK-BR3 and normal MCF10A cell lines. By modulating PTTG1 expression levels, we found that PTTG1 enhances the migratory and invasive properties of breast cancer cells by inducing epithelial to mesenchymal transition, as evidenced by altered morphology and epithelial/mesenchymal cell marker expression patterns and up-regulation of the transcription factor Snail. Notably, down-regulation of PTTG1 also suppressed cancer stem cell population in BT549 cells by decreasing self-renewing ability and tumorigenic capacity, accompanying decreasing CD44(high) CD24(low) cells and Sox2 expression. Up-regulation of PTTG1 had the opposite effects, increasing sphere-forming ability and Sox2 expression. Importantly, PTTG1-mediated malignant tumor properties were due, at least in part, to activation of AKT, known to be a key regulator of both EMT and stemness in cancer cells. Collectively, these results suggest that PTTG1 may represent a new therapeutic target for malignant breast cancer.


Asunto(s)
Biomarcadores de Tumor/biosíntesis , Neoplasias de la Mama/metabolismo , Movimiento Celular , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/biosíntesis , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Antígeno CD24/genética , Antígeno CD24/metabolismo , Línea Celular Tumoral , Regulación hacia Abajo/genética , Activación Enzimática/genética , Femenino , Humanos , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Invasividad Neoplásica , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Securina , Factores de Transcripción de la Familia Snail , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
13.
Cancer Sci ; 104(9): 1172-7, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23714583

RESUMEN

Glioblastoma remains an incurable brain disease due to the prevalence of its recurrence. Considerable evidence suggests that glioma stem-like cells are responsible for glioma relapse after treatment, which commonly involves ionizing radiation. Here, we found that fractionated ionizing radiation (2 Gy/day for 3 days) induced glioma stem-like cell expansion and resistance to anticancer treatment such as cisplatin (50 µM) or taxol (500 nM), or by ionizing radiation (10 Gy) in both glioma cell lines (U87, U373) and patient-derived glioma cells. Of note, concomitant increase of nitric oxide production occurred with the radiation-induced increase of the glioma stem-like cell population through upregulation of inducible nitric oxide synthase (iNOS). In line with this observation, downregulation of iNOS effectively reduced the glioma stem-like cell population and decreased resistance to anticancer treatment. Collectively, our results suggest that targeting iNOS in combination with ionizing radiation might increase the efficacy of radiotherapy for glioma treatment.


Asunto(s)
Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapia , Glioblastoma/patología , Glioblastoma/radioterapia , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/efectos de la radiación , Óxido Nítrico/biosíntesis , Anciano , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Fraccionamiento de la Dosis de Radiación , Regulación hacia Abajo , Resistencia a Antineoplásicos/genética , Femenino , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Células Madre Neoplásicas/metabolismo , Óxido Nítrico/genética , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Radioterapia/efectos adversos , Regulación hacia Arriba
14.
J Cell Sci ; 124(Pt 18): 3084-94, 2011 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-21878493

RESUMEN

Brain tumors frequently recur or progress as focal masses after treatment with ionizing radiation. However, the mechanisms underlying the repopulation of tumor cells after radiation have remained unclear. In this study, we show that cellular signaling from Abelson murine leukemia viral oncogene homolog (Abl) to protein kinase Cδ (PKCδ) is crucial for fractionated-radiation-induced expansion of glioma-initiating cell populations and acquisition of resistance to anticancer treatments. Treatment of human glioma cells with fractionated radiation increased Abl and PKCδ activity, expanded the CD133-positive (CD133(+)) cell population that possesses tumor-initiating potential and induced expression of glioma stem cell markers and self-renewal-related proteins. Moreover, cells treated with fractionated radiation were resistant to anticancer treatments. Small interfering RNA (siRNA)-mediated knockdown of PKCδ expression blocked fractionated-radiation-induced CD133(+) cell expansion and suppressed expression of glioma stem cell markers and self-renewal-related proteins. It also suppressed resistance of glioma cells to anticancer treatments. Similarly, knockdown of Abl led to a decrease in CD133(+) cell populations and restored chemotherapeutic sensitivity. It also attenuated fractionated-radiation-induced PKCδ activation, suggesting that Abl acts upstream of PKCδ. Collectively, these data indicate that fractionated radiation induces an increase in the glioma-initiating cell population, decreases cellular sensitivity to cancer treatment and implicates activation of Abl-PKCδ signaling in both events. These findings provide insights that might prove pivotal in the context of ionising-radiation-based therapeutic interventions for brain tumors.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/radioterapia , Glioma/metabolismo , Glioma/radioterapia , Proteína Quinasa C-delta/metabolismo , Antígeno AC133 , Animales , Antígenos CD/biosíntesis , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Procesos de Crecimiento Celular/genética , Procesos de Crecimiento Celular/efectos de la radiación , Línea Celular Tumoral , Fraccionamiento de la Dosis de Radiación , Resistencia a Antineoplásicos/genética , Glioma/tratamiento farmacológico , Glioma/patología , Glicoproteínas/biosíntesis , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Células Madre Neoplásicas/efectos de la radiación , Proteínas Oncogénicas v-abl/genética , Proteínas Oncogénicas v-abl/metabolismo , Péptidos , Proteína Quinasa C-delta/genética , ARN Interferente Pequeño/genética , Transducción de Señal/genética , Carga Tumoral/genética
15.
Biomedicines ; 11(5)2023 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-37239133

RESUMEN

CTNNAL1 is a protein known to be involved in cell-cell adhesion and cell adhesion. Alterations in the expression or function of CTNNAL1 have been reported to contribute to the development and progression of various types of cancer. In breast cancer, CTNNAL1 has been reported as a cancer suppressor gene, and in melanoma and lung cancer, it has been reported as a cancer driver gene. However, due to a lack of research, its function remains unclear. In this study, it is shown that CTNNAL1 regulates cancer stem cells (CSCs) in lung cancer and glioblastoma and modulates their migration and invasion abilities. CSCs are known to play an important role in the malignant transformation of cancer. They have the ability to resist chemotherapeutic drugs and irradiation, which is a known obstacle to cancer treatment. We found that CTNNAL1 regulates the ability to resist irradiation. In addition, we observed that CTNNAL1 regulates the ability of cells to migrate and invade, a key feature of the epithelial to mesenchymal transition phenomenon associated with cancer metastasis. CTNNAL1 was also involved in the secretion of C-C motif chemokine ligand 2 (CCL2), one of the chemokines. CCL2 plays a role in the recruitment of immune cells to the tumor microenvironment, but in cancer, it is known to influence malignancy and metastasis. CTNNAL1 may be a novel target for treating lung CSCs and glioma stem cells and may be used as a marker of malignancy.

16.
Cancers (Basel) ; 15(23)2023 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-38067227

RESUMEN

Kinesin family member 4A (KIF4A) belongs to the kinesin 4 subfamily of kinesin-related proteins and is involved in the regulation of chromosome condensation and segregation during mitotic cell division. The expression of KIF4A in various types of cancer, including lung, breast, and colon cancer, has been found to be associated with poor prognosis in cancer patients. However, the exact mechanism by which it promotes tumorigenesis is not yet understood. In osteosarcoma, the expression of KIF4A has been shown to be associated with cancer stem cells (CSCs), whereas in breast cancer, it is not associated with the maintenance of CSCs but regulates the migratory ability of cells. In this light, we identified phenotypic phenomena affecting the malignancy of cancer in lung cancer and glioma, and investigated the mechanisms promoting tumorigenesis. As a result, we demonstrated that KIF4A affected lung cancer stem cells (LCSCs) and glioma stem cells (GSCs) and regulated CSC signaling mechanisms. In addition, the migratory ability of cells was regulated by KIF4A, and epithelial-to-mesenchymal transition (EMT) marker proteins were controlled. KIF4A regulated the expression of the secretory factor plasminogen activator inhibitor-1 (PAI-1), demonstrating that it sustains cancer malignancy through an autocrine loop. Taken together, these findings suggest that KIF4A regulates CSCs and EMT, which are involved in cancer recurrence and metastasis, indicating its potential value as a novel therapeutic target and prognostic marker in lung cancer and glioma.

17.
Mol Pharmacol ; 82(3): 400-7, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22648970

RESUMEN

Glioma cells with stem cell properties, termed glioma stem-like cells (GSCs), have been linked to tumor formation, maintenance, and progression and are responsible for the failure of chemotherapy and radiotherapy. Because conventional glioma treatments often fail to eliminate GSCs completely, residual surviving GSCs are able to repopulate the tumor. Compounds that target GSCs might be helpful in overcoming resistance to anticancer treatments in human brain tumors. In this study, we showed that 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (BHP), a new 2-pyrone derivative, suppressed the maintenance of the GSC population in both a glioma cell line and patient-derived glioma cells. Treatment of GSCs with BHP effectively inhibited sphere formation and suppressed the CD133(+) cell population. Treatment with BHP also suppressed expression of the stemness-regulating transcription factors Sox2, Notch2, and ß-catenin in sphere-cultured glioma cells. Treatment of GSCs with BHP significantly suppressed two fundamental characteristics of cancer stem cells: self-renewal and tumorigenicity. BHP treatment dramatically inhibited clone-forming ability at the single-cell level and suppressed in vivo tumor formation. BHP markedly inhibited both phosphoinositide 3-kinase/Akt and Ras/Raf-1/extracellular signal-regulated kinase signaling, which suggests that one or both of these pathways are involved in BHP-induced suppression of GSCs. In addition, treatment with BHP effectively sensitized GSCs to chemotherapy and radiotherapy. Taken together, these results indicate that BHP targets GSCs and enhances their sensitivity to anticancer treatments and suggest that BHP treatment may be useful for treating brain tumors by eliminating GSCs.


Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Pironas/farmacología , Antígeno AC133 , Animales , Antígenos CD/metabolismo , Antineoplásicos/farmacología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Glioma/metabolismo , Glioma/patología , Glicoproteínas/metabolismo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Péptidos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-raf/metabolismo , Receptor Notch2/antagonistas & inhibidores , Receptor Notch2/metabolismo , Factores de Transcripción SOXB1/antagonistas & inhibidores , Factores de Transcripción SOXB1/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , beta Catenina/antagonistas & inhibidores , beta Catenina/metabolismo , Proteínas ras/antagonistas & inhibidores , Proteínas ras/metabolismo
18.
Anticancer Drugs ; 23(1): 43-50, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21849886

RESUMEN

Radiation resistance can be overcome by a combination treatment with chemical modifiers. Here, we showed that treatment with 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (BHP), a new 2-pyrone derivative, in combination with ionizing radiation enhances the sensitivity of human cervical cancer cells to ionizing radiation through overproduction of reactive oxygen species (ROS). The combined treatment with BHP and ionizing radiation caused a decrease in clonogenic survival and an increase in apoptotic cell death in cervical cancer cells. The combined treatment promoted conformational activation of Bax and led to mitochondrial apoptotic cell death. The combination treatment also induced a marked increase in intracellular ROS level. Inhibition of ROS attenuated the radiosensitizing effect of BHP, concurrent with a decrease in Bax activation, a decrease in mitochondrial cell death, and an increase in clonogenic survival. These results indicate that BHP synergistically enhances sensitivity of human cervical cancer cells to ionizing radiation through elevation of intracellular ROS and that ROS-dependent Bax activation is critically involved in the increase in apoptotic cell death induced by the combined treatment with BHP and ionizing radiation.


Asunto(s)
Pironas/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Terapia Combinada , Femenino , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/efectos de la radiación , Piranos , Tolerancia a Radiación/efectos de los fármacos , Radiación Ionizante , Especies Reactivas de Oxígeno/metabolismo , Células Tumorales Cultivadas , Neoplasias del Cuello Uterino/patología , Proteína X Asociada a bcl-2/metabolismo
19.
Toxicol Appl Pharmacol ; 254(1): 32-40, 2011 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-21514314

RESUMEN

A subpopulation of cancer cells with stem cell properties is responsible for tumor maintenance and progression, and may contribute to resistance to anticancer treatments. Thus, compounds that target cancer stem-like cells could be usefully applied to destroy cancer. In this study, we investigated the effect of Eckol, a phlorotannin compound, on stemness and malignancies in glioma stem-like cells. To determine whether Eckol targets glioma stem-like cells, we examined whether Eckol treatment could change the expression levels of glioma stem-like cell markers and self-renewal-related proteins as well as the sphere forming ability, and the sensitivity to anticancer treatments. Alterations in the malignant properties of sphere-derived cells by Eckol were also investigated by soft-agar colony forming assay, by xenograft assay in nude mice, and by cell invasion assay. Treatment of sphere-forming glioma cells with Eckol effectively decreased the sphere formation as well as the CD133(+) cell population. Eckol treatment suppressed expression of the glioma stem-like cell markers and the self-renewal-related proteins without cell death. Moreover, treatment of glioma stem-like cells with Eckol significantly attenuated anchorage-independent growth on soft agar and tumor formation in xenograft mice. Importantly, Eckol treatment effectively reduced the resistance of glioma stem-like cells to ionizing radiation and temozolomide. Treatment of glioma stem-like cells with Eckol markedly blocked both phosphoinositide 3-kinase-Akt and Ras-Raf-1-Erk signaling pathways. These results indicate that the natural phlorotannin Eckol suppresses stemness and malignancies in glioma stem-like cells, and thereby makes glioma stem-like cells more sensitive to anticancer treatments, providing novel therapeutic strategies targeting specifically cancer stem-like cells.


Asunto(s)
Antineoplásicos/farmacología , Dioxinas/farmacología , Glioma/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Animales , Western Blotting , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Citometría de Flujo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Trasplante de Neoplasias , Células Madre Neoplásicas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-raf/metabolismo
20.
Int J Oncol ; 59(4)2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34476496

RESUMEN

Epithelial membrane protein 3 (EMP3) is a transmembrane glycoprotein that contains a peripheral myelin protein 22 domain. EMP3 first received attention as a tumor suppressor, but accumulating evidence has since suggested that it may exhibit a tumor­promoting function. Nonetheless, the biological function of EMP3 remains largely unclear with regards to its role in cancer. Herein, it was shown that EMP3 expression is upregulated in non­small cell lung cancer (NSCLC) cells overexpressing aldehyde dehydrogenase 1 (ALDH1). EMP3 was shown to be involved in cell proliferation, the formation of cancer stem cells (CSCs) and in epithelial­mesenchymal transition (EMT). The ability to resist irradiation, one of the characteristics of CSCs, decreased when the EMP3 mRNA expression was knocked down using small interfering RNA. In addition, when EMP3 knockdown reduced the migratory ability of cells, a characteristic of EMT. Additionally, it was shown that the TGF­ß/Smad signaling axis was a target of EMP3. EMP3 was found to interact with TGF­ß receptor type 2 (TGFBR2) upon TGF­ß stimulation in lung CSCs (LCSC). As a result, binding of EMP3­TGFBR2 regulates TGF­ß/Smad signaling activation and consequently affects CSCs and EMT. Kaplan­Meier analysis results confirmed that patients with high expression of EMP3 had poor survival rates. Taken together, these findings showed that EMP3 may be a potential target for management of LCSCs with high expression of ALDH1, and that EMP3 is involved in TGF­ß/Smad signaling activation where it promotes acquisition of cancerous properties in tumors.


Asunto(s)
Neoplasias Pulmonares/patología , Glicoproteínas de Membrana/fisiología , Células Madre Neoplásicas/fisiología , Factor de Crecimiento Transformador beta/fisiología , Familia de Aldehído Deshidrogenasa 1/fisiología , Línea Celular Tumoral , Transición Epitelial-Mesenquimal , Humanos , Receptor Tipo II de Factor de Crecimiento Transformador beta/fisiología , Transducción de Señal/fisiología , Proteínas Smad/fisiología
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