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Endoplasmic reticulum stress (ERS) is a cellular stress response characterized by excessive contraction of the endoplasmic reticulum (ER). It is a pathological hallmark of many diseases, such as diabetes, obesity, and neurodegenerative diseases. In the unique growth characteristic and varied microenvironment of cancer, high levels of stress are necessary to maintain the rapid proliferation and metastasis of tumor cells. This process is closely related to ERS, which enhances the ability of tumor cells to adapt to unfavorable environments and promotes the malignant progression of cancer. In this paper, we review the roles and mechanisms of ERS in tumor cell proliferation, apoptosis, metastasis, angiogenesis, drug resistance, cellular metabolism, and immune response. We found that ERS can modulate tumor progression via the unfolded protein response (UPR) signaling of IRE1, PERK, and ATF6. Targeting the ERS may be a new strategy to attenuate the protective effects of ERS on cancer. This manuscript explores the potential of ERS-targeted therapies, detailing the mechanisms through which ERS influences cancer progression and highlighting experimental and clinical evidence supporting these strategies. Through this review, we aim to deepen our understanding of the role of ER stress in cancer development and provide new insights for cancer therapy.
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BACKGROUND: Colorectal cancer (CRC) is the second most common malignant tumor worldwide, and its incidence rate increases annually. Early diagnosis and treatment are crucial for improving the prognosis of patients with colorectal cancer. Circular RNAs are noncoding RNAs with a closed-loop structure that play a significant role in tumor development. However, the role of circular RNAs in CRC is poorly understood. METHODS: The circular RNA hsa_circ_0000467 was screened in CRC circRNA microarrays using a bioinformatics analysis, and the expression of hsa_circ_0000467 in CRC tissues was determined by in situ hybridization. The associations between the expression level of hsa_circ_0000467 and the clinical characteristics of CRC patients were evaluated. Then, the role of hsa_circ_0000467 in CRC growth and metastasis was assessed by CCK8 assay, EdU assay, plate colony formation assay, wound healing assay, and Transwell assay in vitro and in a mouse model of CRC in vivo. Proteomic analysis and western blotting were performed to investigate the effect of hsa_circ_0000467 on c-Myc signaling. Polysome profiling, RTâqPCR and dual-luciferase reporter assays were performed to determine the effect of hsa_circ_0000467 on c-Myc translation. RNA pull-down, RNA immunoprecipitation (RIP) and immunofluorescence staining were performed to assess the effect of hsa_circ_0000467 on eIF4A3 distribution. RESULTS: In this study, we found that the circular RNA hsa_circ_0000467 is highly expressed in colorectal cancer and is significantly correlated with poor prognosis in CRC patients. In vitro and in vivo experiments revealed that hsa_circ_0000467 promotes the growth and metastasis of colorectal cancer cells. Mechanistically, hsa_circ_0000467 binds eIF4A3 to suppress its nuclear translocation. In addition, it can also act as a scaffold molecule that binds eIF4A3 and c-Myc mRNA to form complexes in the cytoplasm, thereby promoting the translation of c-Myc. In turn, c-Myc upregulates its downstream targets, including the cell cycle-related factors cyclin D2 and CDK4 and the tight junction-related factor ZEB1, and downregulates E-cadherin, which ultimately promotes the growth and metastasis of CRC. CONCLUSIONS: Our findings revealed that hsa_circRNA_0000467 plays a role in the progression of CRC by promoting eIF4A3-mediated c-Myc translation. This study provides a theoretical basis and molecular target for the diagnosis and treatment of CRC.
Asunto(s)
Proliferación Celular , Neoplasias Colorrectales , Factor 4A Eucariótico de Iniciación , Regulación Neoplásica de la Expresión Génica , Proteínas Proto-Oncogénicas c-myc , ARN Circular , ARN Circular/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Humanos , Factor 4A Eucariótico de Iniciación/metabolismo , Factor 4A Eucariótico de Iniciación/genética , Animales , Ratones , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Progresión de la Enfermedad , Línea Celular Tumoral , Masculino , Pronóstico , Femenino , Biosíntesis de Proteínas , Movimiento Celular/genética , Biomarcadores de Tumor/genética , ARN Helicasas DEAD-boxRESUMEN
Poly (adenosine 5'-diphosphate-ribose) polymerase inhibitors (PARPi) are increasingly important in the treatment of ovarian cancer. However, more than 40% of BRCA1/2-deficient patients do not respond to PARPi, and BRCA wild-type cases do not show obvious benefit. In this study, we demonstrated that progesterone acted synergistically with niraparib in ovarian cancer cells by enhancing niraparib-mediated DNA damage and death regardless of BRCA status. This synergy was validated in an ovarian cancer organoid model and in vivo experiments. Furthermore, we found that progesterone enhances the activity of niraparib in ovarian cancer through inducing ferroptosis by up-regulating palmitoleic acid and causing mitochondrial damage. In clinical cohort, it was observed that progesterone prolonged the survival of patients with ovarian cancer receiving PARPi as second-line maintenance therapy, and high progesterone receptor expression combined with low glutathione peroxidase 4 (GPX4) expression predicted better efficacy of PARPi in patients with ovarian cancer. These findings not only offer new therapeutic strategies for PARPi poor response ovarian cancer but also provide potential molecular markers for predicting the PARPi efficacy.
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DNA damage plays a significant role in the tumorigenesis and progression of the disease. Abnormal DNA repair affects the therapy and prognosis of cancer. In this study, it is demonstrated that the deubiquitinase USP25 promotes non-homologous end joining (NHEJ), which in turn contributes to chemoresistance in cancer. It is shown that USP25 deubiquitinates SHLD2 at the K64 site, which enhances its binding with REV7 and promotes NHEJ. Furthermore, USP25 deficiency impairs NHEJ-mediated DNA repair and reduces class switch recombination (CSR) in USP25-deficient mice. USP25 is overexpressed in a subset of colon cancers. Depletion of USP25 sensitizes colon cancer cells to IR, 5-Fu, and cisplatin. TRIM25 is also identified, an E3 ligase, as the enzyme responsible for degrading USP25. Downregulation of TRIM25 leads to an increase in USP25 levels, which in turn induces chemoresistance in colon cancer cells. Finally, a peptide that disrupts the USP25-SHLD2 interaction is successfully identified, impairing NHEJ and increasing sensitivity to chemotherapy in PDX model. Overall, these findings reveal USP25 as a critical effector of SHLD2 in regulating the NHEJ repair pathway and suggest its potential as a therapeutic target for cancer therapy.
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Roturas del ADN de Doble Cadena , Ubiquitina Tiolesterasa , Animales , Ratones , Roturas del ADN de Doble Cadena/efectos de los fármacos , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo , Humanos , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Modelos Animales de Enfermedad , Reparación del ADN/genética , Reparación del ADN por Unión de Extremidades/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Neoplasias del Colon/tratamiento farmacológico , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismoRESUMEN
Hepatocellular carcinoma (HCC) is a digestive tract cancer with high mortality and poor prognosis, especially in China. Current chemotherapeutic drugs lead to poor prognosis, low efficacy, and high side effects due to weak targeting specificity and rapidly formed multidrug resistance (MDR). Based on the previous studies on the doxorubicin (DOX) formulation for cancer targeting therapy, we developed a novel DOX delivery formulation for the targeting chemotherapy of HCC and DOX resistant HCC. HCSP4 was previously screened and casein kinase 2α (CK2α) was predicted as its specific target on HCC cells in our lab. In the study, miR125a-5p was firstly predicted as an MDR inhibiting miRNA, and then CK2α was validated as the target of HCSP4 and miR125a-5p using CK2α-/-HepG2 cells. Based on the above, an HCC targeting and MDR inhibiting DOX delivery liposomal formulation, HCSP4/Lipo-DOX/miR125a-5p was synthesized and tested for its HCC therapeutic efficacy in vitro. The results showed that the liposomal DOX delivery formulation targeted to HCC cells specifically and sensitively, and presented the satisfied therapeutic efficacy for HCC, particularly for DOX resistant HCC. The potential therapeutic mechanism of the DOX delivery formulation was explored, and the formulation inhibited the expression of MDR-relevant genes including ATP-binding cassette subfamily B member 1 (ABCB1, also known as P-glycoprotein), ATP-binding cassette subfamily C member 5 (ABCC5), enhancer of zeste homolog 2 (EZH2), and ATPase Na+/K+ transporting subunit beta 1 (ATP1B1). Our study presents a novel targeting chemotherapeutic drug formulation for the therapy of HCC, especially for drug resistant HCC, although it is primarily and needs further study in vivo, but provided a new strategy for the development of novel anticancer drugs.
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Carcinoma Hepatocelular , Quinasa de la Caseína II , Doxorrubicina , Resistencia a Antineoplásicos , Liposomas , Neoplasias Hepáticas , Humanos , Doxorrubicina/farmacología , Doxorrubicina/química , Doxorrubicina/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Liposomas/química , Quinasa de la Caseína II/genética , Quinasa de la Caseína II/metabolismo , Quinasa de la Caseína II/antagonistas & inhibidores , Células Hep G2 , Resistencia a Antineoplásicos/efectos de los fármacos , Sistemas de Liberación de Medicamentos , MicroARNs/genéticaRESUMEN
Previous studies have demonstrated that diallyl disulfide (DADS) exhibits potent anti-tumor activity. However, the pharmacological actions of DADS in inhibiting the growth of colorectal cancer (CRC) cells have not been clarified. Herein, we show that DADS treatment impairs the activation of the pentose phosphate pathway (PPP) to decrease PRPP (5-phosphate ribose-1-pyrophosphate) production, enhancing DNA damage and cell apoptosis, and inhibiting the growth of CRC cells. Mechanistically, DADS treatment promoted POU2F1 K48-linked ubiquitination and degradation by attenuating the PI3K/AKT signaling to up-regulate TRIM21 expression in CRC cells. Evidently, TRIM21 interacted with POU2F1, and induced the K272 ubiquitination of POU2F1. The effects of DADS on the enhanced K272 ubiquitination of POU2F1, the PPP flux, PRPP production, DNA damage and cell apoptosis as well as the growth of CRC tumors in vivo were significantly mitigated by TRIM21 silencing or activating the PI3K signaling in CRC cells. Conversely, the effects of DADS were enhanced by TRIM21 over-expression or inhibiting the PI3K/AKT signaling in CRC cells. Collectively, our findings reveal a novel mechanism by which DADS suppresses the growth of CRC by promoting POU2F1 ubiquitination, and may aid in design of novel therapeutic intervention of CRC.
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Ácido 4-Acetamido-4'-isotiocianatostilbeno-2,2'-disulfónico/análogos & derivados , Compuestos Alílicos , Neoplasias Colorrectales , Disulfuros , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Apoptosis/genética , Compuestos Alílicos/farmacología , Compuestos Alílicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Daño del ADN , Factor 1 de Transcripción de Unión a Octámeros/genéticaRESUMEN
Cellular metabolism is the fundamental process by which cells maintain growth and self-renewal. It produces energy, furnishes raw materials, and intermediates for biomolecule synthesis, and modulates enzyme activity to sustain normal cellular functions. Cellular metabolism is the foundation of cellular life processes and plays a regulatory role in various biological functions, including programmed cell death. Ferroptosis is a recently discovered form of iron-dependent programmed cell death. The inhibition of ferroptosis plays a crucial role in tumorigenesis and tumor progression. However, the role of cellular metabolism, particularly glucose and amino acid metabolism, in cancer ferroptosis is not well understood. Here, we reviewed glucose, lipid, amino acid, iron and selenium metabolism involvement in cancer cell ferroptosis to elucidate the impact of different metabolic pathways on this process. Additionally, we provided a detailed overview of agents used to induce cancer ferroptosis. We explained that the metabolism of tumor cells plays a crucial role in maintaining intracellular redox homeostasis and that disrupting the normal metabolic processes in these cells renders them more susceptible to iron-induced cell death, resulting in enhanced tumor cell killing. The combination of ferroptosis inducers and cellular metabolism inhibitors may be a novel approach to future cancer therapy and an important strategy to advance the development of treatments.
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Ferroptosis , Neoplasias , Humanos , Aminoácidos , Glucosa , HierroRESUMEN
One of the key features of cancer is energy metabolic reprogramming which is tightly related to cancer proliferation, invasion, metastasis, and chemotherapy resistance. NcRNAs are a class of RNAs having no protein-coding potential and mainly include microRNAs, lncRNAs and circRNAs. Accumulated evidence has suggested that ncRNAs play an essential role in regulating cancer metabolic reprogramming, and the altered metabolic networks mediated by ncRNAs primarily drive carcinogenesis by regulating the expression of metabolic enzymes and transporter proteins. Importantly, accumulated research has revealed that dysregulated ncRNAs mediate metabolic reprogramming contributing to the generation of therapeutic tolerance. Elucidating the molecular mechanism of ncRNAs in cancer metabolic reprogramming can provide promising metabolism-related therapeutic targets for treatment as well as overcome therapeutic tolerance. In conclusion, this review updates the latest molecular mechanisms of ncRNAs related to cancer metabolic reprogramming.
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Human papillomavirus (HPV) is a class of envelope-free double-stranded DNA virus. HPV infection has been strongly associated with the development of many malignancies, such as cervical, anal and oral cancers. The viral oncoproteins E6 and E7 perform central roles on HPV-induced carcinogenic processes. During tumor development, it usually goes along with the activation of abnormal signaling pathways. E6 and E7 induces changes in cell cycle, proliferation, invasion, metastasis and other biological behaviors by affecting downstream tumor-related signaling pathways, thus promoting malignant transformation of cells and ultimately leading to tumorigenesis and progression. Here, we summarized that E6 and E7 proteins promote HPV-associated tumorigenesis and development by regulating the activation of various tumor-related signaling pathways, for example, the Wnt/ß-catenin, PI3K/Akt, and NF-kB signaling pathway. We also discussed the importance of HPV-encoded E6 and E7 and their regulated tumor-related signaling pathways for the diagnosis and effective treatment of HPV-associated tumors.
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Proteínas Oncogénicas Virales , Infecciones por Papillomavirus , Neoplasias del Cuello Uterino , Humanos , Femenino , Virus del Papiloma Humano , Infecciones por Papillomavirus/complicaciones , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Oncogénicas Virales/genética , Transducción de Señal/genética , Neoplasias del Cuello Uterino/genética , Carcinogénesis , Proteínas E7 de Papillomavirus/genéticaRESUMEN
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an aggressive and deadly malignancy characterized by late-stage diagnosis, therapy resistance, and a poor 5-year survival rate. Finding novel therapeutic targets and their inhibitors for ESCC prevention and therapy is urgently needed. METHODS: We investigated the proviral integration site for maloney murine leukemia virus 3 (Pim-3) protein levels using immunohistochemistry. Using Methyl Thiazolyl Tetrazolium and clone formation assay, we verified the function of Pim-3 in cell proliferation. The binding and inhibition of Pim-3 by corynoline were verified by computer docking, pull-down assay, cellular thermal shift assay, and kinase assay. Cell proliferation, Western blot, and a patient-derived xenograft tumor model were performed to elucidate the mechanism of corynoline inhibiting ESCC growth. RESULTS: Pim-3 was highly expressed in ESCC and played an oncogenic role. The augmentation of Pim-3 enhanced cell proliferation and tumor development by phosphorylating mitogen-activated protein kinase 1 (MAPK1) at T185 and Y187. The deletion of Pim-3 induced apoptosis with upregulated cleaved caspase-9 and lower Bcl2 associated agonist of cell death (BAD) phosphorylation at S112. Additionally, binding assays demonstrated corynoline directly bound with Pim-3, inhibiting its activity, and suppressing ESCC growth. CONCLUSIONS: Our findings suggest that Pim-3 promotes ESCC progression. Corynoline inhibits ESCC progression through targeting Pim-3.
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Alcaloides de Berberina , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Animales , Ratones , Humanos , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/metabolismo , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Movimiento Celular , ApoptosisRESUMEN
The homeobox (HOX) gene family plays a fundamental role in carcinogenesis. However, the oncogenic mechanism of HOXC10 in head and neck squamous cell carcinoma (HNSCC) remains unclear. In the present study, it was revealed that HOXC10 expression was significantly higher in HNSCC tissues than in adjacent tissues, and a high level of HOXC10 was closely associated with worse clinical outcomes. HOXC10 overexpression promoted HNSCC cell proliferation, migration, and invasion, both in vitro and in vivo. Mechanistically, chromatin immunoprecipitation sequencing revealed that HOXC10 drove the transcriptional activation of a disintegrin and metalloproteinase 17 (ADAM17), and the ADAM17/epidermal growth factor receptor (EGFR)/ERK1/2 signaling pathway facilitating the proliferation of HNSCC. Furthermore, mass spectrometric analysis indicated that HOXC10 interacted with ribosomal protein S15A (RPS15A) and enhanced RPS15A protein expression, activating the Wnt/ßcatenin pathway and contributing to invasion and metastasis of HNSCC. Additionally, the methylated RNA immune precipitation and RNA antisense purification assays showed that N6methyladenosine (m6A) writer, methyltransferaselike 3, catalyzed m6A modification of the HOXC10 transcript, m6A reader insulin like growth factor 2 mRNA binding protein (IGF2BP)1 and IGF2BP3 involved in recognizing and stabilizing m6Atagged HOXC10 mRNA. In summary, the present study identified HOXC10 as a promising candidate oncogene in HNSCC. The m6A modificationmediated HOXC10 promoted proliferation, migration, and invasion of HNSCC through coactivation of ADAM17/EGFR and Wnt/ßcatenin signaling, providing a novel diagnostic and prognostic biomarker and a potential therapeutic target for HNSCC.
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Proteína ADAM17 , Genes Homeobox , Neoplasias de Cabeza y Cuello , Proteínas de Homeodominio , Humanos , Proteína ADAM17/genética , beta Catenina/genética , beta Catenina/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/genética , Proteínas de Homeodominio/metabolismo , ARN , ARN Mensajero , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Vía de Señalización Wnt/genética , Metilación de ARNRESUMEN
Ferritinophagy, a process involving selective autophagy of ferritin facilitated by nuclear receptor coactivator 4 (NCOA4), entails the recognition of ferritin by NCOA4 and subsequent delivery to the autophagosome. Within the autophagosome, ferritin undergoes degradation, leading to the release of iron in the lysosome. It is worth noting that excessive iron levels can trigger cell death. Recent evidence has elucidated the significant roles played by ferritinophagy and ferroptosis in regulation the initiation and progression of cancer. Given the crucial role of ferritinophagy in tumor biology, it may serve as a potential target for future anti-tumor therapeutic interventions. In this study, we have provided the distinctive features of ferritinophagy and its distinctions from ferroptosis. Moreover, we have briefly examined the fundamental regulatory mechanisms of ferritinophagy, encompassing the involvement of the specific receptor NCOA4, the Nrf2/HO-1 signaling and other pathways. Subsequently, we have synthesized the current understanding of the impact of ferritinophagy on cancer progression and its potential therapeutic applications, with a particular emphasis on the utilization of chemotherapy, nanomaterials, and immunotherapy to target the ferritinophagy pathway for anti-tumor purposes.