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In tumors, nutrient availability and metabolism are known to be important modulators of growth signaling. However, it remains elusive whether cancer cells that are growing out in the metastatic niche rely on the same nutrients and metabolic pathways to activate growth signaling as cancer cells within the primary tumor. We discovered that breast-cancer-derived lung metastases, but not the corresponding primary breast tumors, use the serine biosynthesis pathway to support mTORC1 growth signaling. Mechanistically, pyruvate uptake through Mct2 supported mTORC1 signaling by fueling serine biosynthesis-derived α-ketoglutarate production in breast-cancer-derived lung metastases. Consequently, expression of the serine biosynthesis enzyme PHGDH was required for sensitivity to the mTORC1 inhibitor rapamycin in breast-cancer-derived lung tumors, but not in primary breast tumors. In summary, we provide in vivo evidence that the metabolic and nutrient requirements to activate growth signaling differ between the lung metastatic niche and the primary breast cancer site.
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Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Neoplasias Mamarias Experimentales/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Fosfoglicerato-Deshidrogenasa/genética , Serina/biosíntesis , Animales , Antibióticos Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Femenino , Humanos , Ácidos Cetoglutáricos/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Fosfoglicerato-Deshidrogenasa/antagonistas & inhibidores , Fosfoglicerato-Deshidrogenasa/metabolismo , Ácido Pirúvico/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Sirolimus/farmacologíaRESUMEN
Extracellular matrix (ECM) is a major component of the tumor environment, promoting the establishment of a pro-invasive behavior. Such environment is supported by both tumor- and stromal-derived metabolites, particularly lactate. In prostate cancer (PCa), cancer-associated fibroblasts (CAFs) are major contributors of secreted lactate, able to impact on metabolic and transcriptional regulation in cancer cells. Here, we describe a mechanism by which CAF-secreted lactate promotes in PCa cells the expression of genes coding for the collagen family. Lactate-exploiting PCa cells rely on increased α-ketoglutarate (α-KG) which activates the α-KG-dependent collagen prolyl-4-hydroxylase (P4HA1) to support collagen hydroxylation. De novo synthetized collagen plays a signaling role by activating discoidin domain receptor 1 (DDR1), supporting stem-like and invasive features of PCa cells. Inhibition of lactate-induced collagen hydroxylation and DDR1 activation reduces the metastatic colonization of PCa cells. Overall, these results provide a new understanding of the link between collagen remodeling/signaling and the nutrient environment exploited by PCa.
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Colágeno , Matriz Extracelular , Ácido Láctico , Metástasis de la Neoplasia , Neoplasias de la Próstata , Masculino , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/genética , Humanos , Matriz Extracelular/metabolismo , Colágeno/metabolismo , Ácido Láctico/metabolismo , Línea Celular Tumoral , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Transducción de Señal , Regulación Neoplásica de la Expresión Génica , Animales , Ratones , Microambiente Tumoral , Ácidos Cetoglutáricos/metabolismo , HidroxilaciónRESUMEN
Metabolism is at the cornerstone of all cellular functions and mounting evidence of its deregulation in different diseases emphasizes the importance of a comprehensive understanding of metabolic regulation at the whole-organism level. Stable-isotope measurements are a powerful tool for probing cellular metabolism and, as a result, are increasingly used to study metabolism in in vivo settings. The additional complexity of in vivo metabolic measurements requires paying special attention to experimental design and data interpretation. Here, we review recent work where in vivo stable-isotope measurements have been used to address relevant biological questions within an in vivo context, summarize different experimental and data interpretation approaches and their limitations, and discuss future opportunities in the field.
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Células/metabolismo , Marcaje Isotópico , Animales , HumanosRESUMEN
Post-translational modifications affect protein biology under physiological and pathological conditions. Efficient methods for the preparation of peptides and proteins carrying defined, homogeneous modifications are fundamental tools for investigating these functions. In the case of mucinâ 1 (MUC1), an altered glycosylation pattern is observed in carcinogenesis. To better understand the role of MUC1 glycosylation in the interactions and adhesion of cancer cells, we prepared a panel of homogeneously O-glycosylated MUC1 peptides by using a quantitative chemoenzymatic approach. Cell-adhesion experiments with MCF-7 cancer cells on surfaces carrying up to six differently glycosylated MUC1 peptides demonstrated that different glycans have a significant impact on adhesion. This finding suggests a distinct role for MUC1 glycosylation patterns in cancer cell migration and/or invasion. To decipher the molecular mechanism for the observed adhesion, we investigated the conformation of the glycosylated MUC1 peptides by NMR spectroscopy. These experiments revealed only minor differences in peptide structure, therefore clearly relating the adhesion behaviour to the type and number of glycans linked to MUC1.
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Glicopéptidos , Mucina-1 , Mucina-1/química , Glicopéptidos/química , Glicosilación , Adhesión Celular , Péptidos/química , Proteínas/metabolismo , PolisacáridosRESUMEN
BACKGROUND & AIMS: Little is known about the metabolic regulation of cancer stem cells (CSCs) in cholangiocarcinoma (CCA). We analyzed whether mitochondrial-dependent metabolism and related signaling pathways contribute to stemness in CCA. METHODS: The stem-like subset was enriched by sphere culture (SPH) in human intrahepatic CCA cells (HUCCT1 and CCLP1) and compared to cells cultured in monolayer. Extracellular flux analysis was examined by Seahorse technology and high-resolution respirometry. In patients with CCA, expression of factors related to mitochondrial metabolism was analyzed for possible correlation with clinical parameters. RESULTS: Metabolic analyses revealed a more efficient respiratory phenotype in CCA-SPH than in monolayers, due to mitochondrial oxidative phosphorylation. CCA-SPH showed high mitochondrial membrane potential and elevated mitochondrial mass, and over-expressed peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α, a master regulator of mitochondrial biogenesis. Targeting mitochondrial complex I in CCA-SPH using metformin, or PGC-1α silencing or pharmacologic inhibition (SR-18292), impaired spherogenicity and expression of markers related to the CSC phenotype, pluripotency, and epithelial-mesenchymal transition. In mice with tumor xenografts generated by injection of CCA-SPH, administration of metformin or SR-18292 significantly reduced tumor growth and determined a phenotype more similar to tumors originated from cells grown in monolayer. In patients with CCA, expression of PGC-1α correlated with expression of mitochondrial complex II and of stem-like genes. Patients with higher PGC-1α expression by immunostaining had lower overall and progression-free survival, increased angioinvasion and faster recurrence. In GSEA analysis, patients with CCA and high levels of mitochondrial complex II had shorter overall survival and time to recurrence. CONCLUSIONS: The CCA stem-subset has a more efficient respiratory phenotype and depends on mitochondrial oxidative metabolism and PGC-1α to maintain CSC features. LAY SUMMARY: The growth of many cancers is sustained by a specific type of cells with more embryonic characteristics, termed 'cancer stem cells'. These cells have been described in cholangiocarcinoma, a type of liver cancer with poor prognosis and limited therapeutic approaches. We demonstrate that cancer stem cells in cholangiocarcinoma have different metabolic features, and use mitochondria, an organelle located within the cells, as the major source of energy. We also identify PGC-1α, a molecule which regulates the biology of mitochondria, as a possible new target to be explored for developing new treatments for cholangiocarcinoma.
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Neoplasias de los Conductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Mitocondrias/metabolismo , Células Madre Neoplásicas/metabolismo , Fosforilación Oxidativa , Fenotipo , Transducción de Señal/genética , Animales , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/patología , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Línea Celular Tumoral , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/patología , Complejo II de Transporte de Electrones/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Silenciador del Gen , Humanos , Indoles/administración & dosificación , Masculino , Metformina/administración & dosificación , Ratones , Ratones Endogámicos NOD , Ratones SCID , Fosforilación Oxidativa/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/antagonistas & inhibidores , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Supervivencia sin Progresión , Propanoles/administración & dosificación , Transducción de Señal/efectos de los fármacos , Transfección , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Chemoresistance is the primary cause of chemotherapy failure. Compelling evidence shows that micro RNAs (miRNAs) contribute to reprogram cancer cells toward a resistant phenotype. We investigate the role of miRNAs in the response to acute treatment with 5-FU in colon cancer-resistant cells. We performed a global gene expression profile for the entire miRNA genome and found a change in the expression of four miRNAs following acute treatment with 5-FU. Among them, we focused on miR-210-3p, previously described as a key regulator of DNA damage repair mechanisms and mitochondrial metabolism. We show that miR-210-3p downregulation enables resistant cells to counteract the toxic effect of the drug increasing the expression of RAD-52 protein, responsible for DNA damage repair. Moreover, miR-210-3p downregulation enhances oxidative phosphorylation (OXPHOS), increasing the expression levels of succinate dehydrogenase subunits D, decreasing intracellular succinate levels and inhibiting HIF-1α expression. Altogether, these adaptations lead to increased cells survival following drug exposure. These evidence suggest that miR-210-3p downregulation following 5-FU sustains DNA damage repair and metabolic adaptation to counteract drug treatment.
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Neoplasias del Colon/genética , Reparación del ADN , Resistencia a Antineoplásicos/efectos de los fármacos , Fluorouracilo/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , MicroARNs/genética , Adaptación Fisiológica/efectos de los fármacos , Adaptación Fisiológica/genética , Antimetabolitos Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Neoplasias del Colon/metabolismo , Daño del ADN , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Perfilación de la Expresión Génica/métodos , Células HT29 , HumanosRESUMEN
LMW-PTP has been associated with the development of colorectal cancer (CRC) and with the resistance to chemotherapy in cancer cells. To clarify its role in vivo, we studied LMW-PTP expression in Pirc rats (F344/NTac-Apc am1137 ), genetically prone to CRC and resistant to apoptosis. In the morphologically normal mucosa (NM) of Pirc rats, a dramatic over-expression of LMW-PTP was found compared to wt rats (about 60 times higher). Moreover, LMW-PTP levels further increase in spontaneously developed Pirc colon tumors. To understand if and how LMW-PTP affects resistance to apoptosis, we studied CRC cell lines, sensitive (HT29 and HCT-116), or resistant (HT29R, HCT116R) to 5-Fluorouracil (5-FU): resistant cells over-express LMW-PTP. When resistant cells were challenged with morin, a polyphenol inhibiting LMW-PTP, a fast and dose-related down-regulation of LMW-PTP was observed. 5-FU and morin co-treatment dramatically decreased cell viability, increased apoptosis, and significantly impaired self-renewal ability of all the cancer cell lines we have studied. Similarly, we observed that, in Pirc rats, one-week morin administration (50 mg/kg) down-regulated LMW-PTP and restored the apoptotic response to 5-FU in the NM. Finally, administration of morin for a longer period led to a significant reduction in colon precancerous lesions, together with a down-regulation of LMW-PTP. Taken together, these results document the involvement of LMW-PTP in the process of CRC in vitro and in vivo. Morin treatment may be envisaged as a system to increase the sensitivity to chemotherapy and to prevent carcinogenesis.
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Carcinogénesis/patología , Colon/patología , Neoplasias del Colon/patología , Modelos Animales de Enfermedad , Flavonoides/farmacología , Genes APC , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Animales , Antioxidantes/farmacología , Carcinogénesis/inducido químicamente , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Colon/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/etiología , Técnicas In Vitro , Masculino , Proteínas Tirosina Fosfatasas/genética , Proteínas Proto-Oncogénicas/genética , Ratas , Ratas Endogámicas F344RESUMEN
Resistance to anticancer therapy still represents one of the main obstacles to cancer treatment. Numerous components of the tumor microenvironment (TME) contribute significantly to the acquisition of drug resistance. Microenvironmental pressures arising during cancer evolution foster tumor heterogeneity (TH) and facilitate the emergence of drug-resistant clones. In particular, metabolic pressures arising in the TME may favor epigenetic adaptations supporting the acquisition of persistence features in tumor cells. Tumor-persistent cells (TPCs) are characterized by high phenotypic and metabolic plasticity, representing a noticeable advantage in chemo- and radio-resistance. Understanding the crosslink between the evolution of metabolic pressures in the TME, epigenetics, and TPC evolution is significant for developing novel therapeutic strategies specifically targeting TPC vulnerabilities to overcome drug resistance.
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Neoplasias , Humanos , Neoplasias/patología , Microambiente TumoralRESUMEN
The success of disseminating cancer cells (DTCs) at specific metastatic sites is influenced by several metabolic factors. Even before DTCs arrival, metabolic conditioning from the primary tumor participates in creating a favorable premetastatic niche at distant organs. In addition, DTCs adjust their metabolism to better survive along the metastatic journey and successfully colonize their ultimate destination. However, the idea that the environment of the target organs may metabolically impact the metastatic fate is often underestimated. Here, we review the coexistence of two distinct strategies by which cancer cells shape and/or adapt to the metabolic profile of colonized tissues, ultimately creating a proper soil for their seeding and proliferation.
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Type 2 diabetes mellitus (T2DM) is a complex disease characterized by impaired glucose homeostasis and serious long-term complications. First-line therapeutic options for T2DM treatment are monodrug therapies, often replaced by multidrug therapies to ensure that non-responding patients maintain target glycemia levels. The use of multitarget drugs instead of mono- or multidrug therapies has been emerging as a main strategy to treat multifactorial diseases, including T2DM. Therefore, modern drug discovery in its early stages aims to identify potential modulators for multiple targets; for this purpose, exploration of the chemical space of natural products represents a powerful tool. Our study demonstrates that avarone, a sesquiterpene quinone obtained from the sponge Dysidea avara, is capable of inhibiting in vitro PTP1B, the main negative regulator of the insulin receptor, while it improves insulin sensitivity, and mitochondria activity in C2C12 cells. We observe that when avarone is administered alone, it acts as an insulin-mimetic agent. In addition, we show that avarone acts as a tight binding inhibitor of aldose reductase (AKR1B1), the enzyme involved in the development of diabetic complications. Overall, avarone could be proposed as a novel natural hit to be developed as a multitarget drug for diabetes and its pathological complications.
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In the early stages of carcinogenesis, the transformed cells become "invisible" to the immune system. From this moment on, the evolution of the tumor depends essentially on the genotype of the primitive cancer cells and their subsequent genetic drift. The role of the immune system in blocking tumor progression from the earliest stages is largely underestimated because by the time tumors are clinically detectable, the immune system has already completely failed its task. Therefore, a clinical treatment capable of restoring the natural anti-tumor role of the immune system could prove to be the "ultimate weapon" against cancer. Herein, we propose a novel therapeutic approach for the treatment of solid cancer that exploits the capability of activated monocytes to transfer major histocompatibility complex I (MHC-I) molecules bound to antigenic peptides to cancer cells using microvesicles as cargo, making tumor cells target of a "natural" CD8+ T lymphocyte cytotoxic response.
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A new series of analogues or derivatives of the previously reported PPARα/γ dual agonist LT175 allowed the identification of ligand 10, which was able to potently activate both PPARα and -γ subtypes as full and partial agonists, respectively. Docking studies were performed to provide a molecular explanation for this different behavior on the two different targets. In vivo experiments showed that this compound induced a significant reduction in blood glucose and lipid levels in an STZ-induced diabetic mouse model displaying no toxic effects on bone, kidney, and liver. By examining in depth the antihyperglycemic activity of 10, we found out that it produced a slight but significant inhibition of the mitochondrial pyruvate carrier, acting also through insulin-independent mechanisms. This is the first example of a PPARα/γ dual agonist reported to show this inhibitory effect representing, therefore, the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes.
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Diabetes Mellitus Tipo 2 , PPAR alfa , Ratones , Animales , PPAR alfa/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Transportadores de Ácidos Monocarboxílicos , Agonistas de PPAR-gamma , PPAR gamma/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéuticoRESUMEN
Tumor relapse represents one of the main obstacles to cancer treatment. Many patients experience cancer relapse even decades from the primary tumor eradication, developing more aggressive and metastatic disease. This phenomenon is associated with the emergence of dormant cancer cells, characterized by cell cycle arrest and largely insensitive to conventional anti-cancer therapies. These rare and elusive cells may regain proliferative abilities upon the induction of cell-intrinsic and extrinsic factors, thus fueling tumor re-growth and metastasis formation. The molecular mechanisms underlying the maintenance of resistant dormant cells and their awakening are intriguing but, currently, still largely unknown. However, increasing evidence recently underlined a strong dependency of cell cycle progression to metabolic adaptations of cancer cells. Even if dormant cells are frequently characterized by a general metabolic slowdown and an increased ability to cope with oxidative stress, different factors, such as extracellular matrix composition, stromal cells influence, and nutrient availability, may dictate specific changes in dormant cells, finally resulting in tumor relapse. The main topic of this review is deciphering the role of the metabolic pathways involved in tumor cells dormancy to provide new strategies for selectively targeting these cells to prevent fatal recurrence and maximize therapeutic benefit.
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Oil production waste products (OPWPs) derive from olive mill and represent a crucial environmental problem due to their high polyphenolic content able to pollute the ground. One option to reduce the OPWPs' environmental impact is to exploit polyphenols' biological properties. We sought to analyze the transcriptomic variations of colorectal cancer cells exposed to the OPWPs extracts and hydroxytyrosol, the major component, to recognize unknown and ill-defined characteristics. Among the top affected pathways identified by GSEA, we focused on oxidative phosphorylation in an in vitro system. Colorectal cancer HCT116 and LoVo cells treated with hydroxytyrosol or OPWPs extracts showed enhancement of the respiratory chain complexes' protein levels, ATP production and membrane potential, suggesting stimulation of mitochondrial functions. The major proteins involved in mitochondrial biogenesis and fusion events of mitochondrial dynamics were positively affected, as by Western blot, fostering increase of the mitochondrial mass organized in a network of elongated organelles. Mechanistically, we proved that PPARγ mediates the effects as they are mimicked by a specific ligand and impaired by a specific inhibitor. OPWP extracts and hydroxytyrosol, thus, promote mitochondrial functionality via a feed-forward regulatory loop involving the PPARγ/PGC-1α axis. These results support their use in functional foods and as adjuvants in cancer therapy.
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Neoplasias Colorrectales , Residuos , Humanos , PPAR gamma/metabolismo , Transcriptoma , Extractos Vegetales/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genéticaRESUMEN
In oncology, the occurrence of distant metastases often marks the transition from curative to palliative care. Such outcome is highly predictable for breast cancer patients, even if tumors are detected early, and there is no specific treatment to prevent metastasis. Previous observations indicated that cancer cell mitochondria are bioenergetic sensors of the tumor microenvironment that produce superoxide to promote evasion. Here, we tested whether mitochondria-targeted antioxidant MitoQ is capable to prevent metastasis in the MDA-MB-231 model of triple-negative human breast cancer in mice and in the MMTV-PyMT model of spontaneously metastatic mouse breast cancer. At clinically relevant doses, we report that MitoQ not only prevented metastatic take and dissemination, but also local recurrence after surgery. We further provide in vitro evidence that MitoQ does not interfere with conventional chemotherapies used to treat breast cancer patients. Since MitoQ already successfully passed Phase I safety clinical trials, our preclinical data collectively provide a strong incentive to test this drug for the prevention of cancer dissemination and relapse in clinical trials with breast cancer patients.
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5-Fluorouracil (5-FU) is a key component of chemotherapy for colorectal cancer (CRC). 5-FU efficacy is established by intracellular levels of folate cofactors and DNA damage repair strategies. However, drug resistance still represents a major challenge. Here, we report that alterations in serine metabolism affect 5-FU sensitivity in in vitro and in vivo CRC models. In particular, 5-FU-resistant CRC cells display a strong serine dependency achieved either by upregulating endogenous serine synthesis or increasing exogenous serine uptake. Importantly, regardless of the serine feeder strategy, serine hydroxymethyltransferase-2 (SHMT2)-driven compartmentalization of one-carbon metabolism inside the mitochondria represents a specific adaptation of resistant cells to support purine biosynthesis and potentiate DNA damage response. Interfering with serine availability or affecting its mitochondrial metabolism revert 5-FU resistance. These data disclose a relevant mechanism of mitochondrial serine use supporting 5-FU resistance in CRC and provide perspectives for therapeutic approaches.
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Neoplasias Colorrectales , Neoplasias , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Resistencia a Antineoplásicos/genética , Fluorouracilo/metabolismo , Fluorouracilo/farmacología , Humanos , Mitocondrias/metabolismo , Neoplasias/metabolismo , Nucleótidos/metabolismo , Serina/metabolismoRESUMEN
Cancer progression is supported by the cross-talk between tumor cells and the surrounding stroma. In this context, senescent cells in the tumor microenvironment contribute to the development of a pro-inflammatory milieu and the acquisition of aggressive traits by cancer cells. Anticancer treatments induce cellular senescence (therapy-induced senescence, TIS) in both tumor and non-cancerous cells, contributing to many detrimental side effects of therapies. Thus, we focused on the effects of chemotherapy on the stromal compartment of prostate and ovarian cancer. We demonstrated that anticancer chemotherapeutics, regardless of their specific mechanism of action, promote a senescent phenotype in stromal fibroblasts, resulting in metabolic alterations and secretion of paracrine factors, sustaining the invasive and clonogenic potential of both prostate and ovarian cancer cells. The clearance of senescent stromal cells, through senolytic drug treatment, reverts the malignant phenotype of tumor cells. The clinical relevance of TIS was validated in ovarian and prostate cancer patients, highlighting increased accumulation of lipofuscin aggregates, a marker of the senescent phenotype, in the stromal compartment of tissues from chemotherapy-treated patients. These data provide new insights into the potential efficacy of combining traditional anticancer strategies with innovative senotherapy to potentiate anticancer treatments and overcome the adverse effects of chemotherapy.
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Neoplasias Ováricas , Neoplasias de la Próstata , Humanos , Masculino , Femenino , Neoplasias Ováricas/genética , Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Fenotipo , Microambiente TumoralRESUMEN
To successfully generate distant metastases, metastatic progenitor cells must simultaneously possess mesenchymal characteristics, resist to anoïkis, migrate and invade directionally, resist to redox and shear stresses in the systemic circulation, and possess stem cell characteristics. These cells primarily originate from metabolically hostile areas of the primary tumor, where oxygen and nutrient deprivation, together with metabolic waste accumulation, exert a strong selection pressure promoting evasion. Here, we followed the hypothesis according to which metastasis as a whole implies the existence of metabolic sensors. Among others, mitochondria are singled out as a major source of superoxide that supports the metastatic phenotype. Molecularly, stressed cancer cells increase mitochondrial superoxide production, which activates the transforming growth factor-ß pathway through src directly within mitochondria, ultimately activating focal adhesion kinase Pyk2. The existence of mitochondria-targeted antioxidants constitutes an opportunity to interfere with the metastatic process. Here, using aggressive triple-negative and HER2-positive human breast cancer cell lines as models, we report that MitoQ inhibits all the metastatic traits that we tested in vitro. Compared to other mitochondria-targeted antioxidants, MitoQ already successfully passed Phase I safety clinical trials, which provides an important incentive for future preclinical and clinical evaluations of this drug for the prevention of breast cancer metastasis.
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Overcoming anticancer drug resistance is a major challenge in cancer therapy, requiring innovative strategies that consider the extensive tumor heterogeneity and adaptability. We provide recent evidence highlighting the key role of amino acid (AA) metabolic reprogramming in cancer cells and the supportive microenvironment in driving resistance to anticancer therapies. AAs sustain the acquisition of anticancer resistance by providing essential building blocks for biosynthetic pathways and for maintaining a balanced redox status, and modulating the epigenetic profile of both malignant and non-malignant cells. In addition, AAs support the reduced intrinsic susceptibility of cancer stem cells to antineoplastic therapies. These findings shed new light on the possibility of targeting nonresponding tumors by modulating AA availability through pharmacological or dietary interventions.
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Aminoácidos/metabolismo , Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Células Madre Neoplásicas/metabolismo , Microambiente Tumoral/efectos de los fármacos , Animales , Antineoplásicos/uso terapéutico , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Humanos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
miR-27a plays a driver role in rewiring tumor cell metabolism. We searched for new miR-27a targets that could affect mitochondria and identified FOXJ3, an apical factor of mitochondrial biogenesis. We analyzed FOXJ3 levels in an in vitro cell model system that was genetically modified for miR-27a expression and validated it as an miR-27a target. We showed that the miR-27a/FOXJ3 axis down-modulates mitochondrial biogenesis and other key members of the pathway, implying multiple levels of control. As assessed by specific markers, the miR-27a/FOXJ3 axis also dysregulates mitochondrial dynamics, resulting in fewer, short, and punctate organelles. Consistently, in high miR-27a-/low FOXJ3-expressing cells, mitochondria are functionally characterized by lower superoxide production, respiration capacity, and membrane potential, as evaluated by OCR assays and confocal microscopy. The analysis of a mouse xenograft model confirmed FOXJ3 as a target and suggested that the miR-27a/FOXJ3 axis affects mitochondrial abundance in vivo. A survey of the TCGA-COADREAD dataset supported the inverse relationship of FOXJ3 with miR-27a and reinforced cellular component organization or biogenesis as the most affected pathway. The miR-27a/FOXJ3 axis acts as a central hub in regulating mitochondrial homeostasis. Its discovery paves the way for new therapeutic strategies aimed at restraining tumor growth by targeting mitochondrial activities.