Metabolic adaptations play a key role in fueling tumor growth. However, less is known regarding the metabolic changes that promote cancer progression to metastatic disease. Herein, we reveal that ...breast cancer cells that preferentially metastasize to the lung or bone display relatively high expression of PGC-1α compared with those that metastasize to the liver. PGC-1α promotes breast cancer cell migration and invasion in vitro and augments lung metastasis in vivo. Pro-metastatic capabilities of PGC-1α are linked to enhanced global bioenergetic capacity, facilitating the ability to cope with bioenergetic disruptors like biguanides. Indeed, biguanides fail to mitigate the PGC-1α-dependent lung metastatic phenotype and PGC-1α confers resistance to stepwise increases in metformin concentration. Overall, our results reveal that PGC-1α stimulates bioenergetic potential, which promotes breast cancer metastasis and facilitates adaptation to metabolic drugs.
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•PGC-1α expression is enriched in breast cancer cells that metastasize to lung and bone•PGC-1α functionally promotes breast cancer metastasis•PGC-1α augments global bioenergetic capacity•PGC-1α confers resistance to bioenergetic disruptors
Andrzejewski et al. show that PGC-1α promotes breast cancer metastasis and increases global bioenergetic capacity, which enables breast cancer cells to overcome the metabolically demanding metastatic process. Cancer cells with elevated PGC-1α activity are resistant to bioenergetic disruptors, such as metformin.
Despite its importance in human cancers, including colorectal cancers (CRC), oncogenic KRAS has been extremely challenging to target therapeutically. To identify potential vulnerabilities in ...KRAS-mutated CRC, we characterize the impact of oncogenic KRAS on the cell surface of intestinal epithelial cells. Here we show that oncogenic KRAS alters the expression of a myriad of cell-surface proteins implicated in diverse biological functions, and identify many potential surface-accessible therapeutic targets. Cell surface-based loss-of-function screens reveal that ATP7A, a copper-exporter upregulated by mutant KRAS, is essential for neoplastic growth. ATP7A is upregulated at the surface of KRAS-mutated CRC, and protects cells from excess copper-ion toxicity. We find that KRAS-mutated cells acquire copper via a non-canonical mechanism involving macropinocytosis, which appears to be required to support their growth. Together, these results indicate that copper bioavailability is a KRAS-selective vulnerability that could be exploited for the treatment of KRAS-mutated neoplasms.
The mammalian/mechanistic target of rapamycin (mTOR) is a key component of cellular metabolism that integrates nutrient sensing with cellular processes that fuel cell growth and proliferation. ...Although the involvement of the mTOR pathway in regulating life span and aging has been studied extensively in the last decade, the underpinning mechanisms remain elusive. In this review, we highlight the emerging insights that link mTOR to various processes related to aging, such as nutrient sensing, maintenance of proteostasis, autophagy, mitochondrial dysfunction, cellular senescence, and decline in stem cell function.
Reprogramming of cellular metabolism plays a central role in fueling malignant transformation, and AMPK and the PGC-1α/ERRα axis are key regulators of this process. The intersection of ...gene-expression and binding-event datasets for breast cancer cells shows that activation of AMPK significantly increases the expression of PGC-1α/ERRα and promotes the binding of ERRα to its cognate sites. Unexpectedly, the data also reveal that ERRα, in concert with PGC-1α, negatively regulates the expression of several one-carbon metabolism genes, resulting in substantial perturbations in purine biosynthesis. This PGC-1α/ERRα-mediated repression of one-carbon metabolism promotes the sensitivity of breast cancer cells and tumors to the anti-folate drug methotrexate. These data implicate the PGC-1α/ERRα axis as a core regulatory node of folate cycle metabolism and further suggest that activators of AMPK could be used to modulate this pathway in cancer.
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•The PGC-1α/ERRα axis is a key effector of AMPK metabolic reprogramming in cancer•The PGC-1α/ERRα axis represses folate cycle metabolism•The PGC-1α/ERRα axis decreases purine biosynthesis•The PGC-1α/ERRα axis sensitizes cells and tumors to anti-folate therapy
Audet-Walsh et al. demonstrate that PGC-1α, in concert with ERRα, is a key downstream mediator of AMPK metabolic reprogramming in cancer cells. They also uncover that the PGC-1α/ERRα axis acts as a repressor of folate cycle metabolism and purine biosynthesis, sensitizing breast cancer cells to anti-folate therapy.
•Canagliflozin constrains cell proliferation in the absence of glucose.•Canagliflozin modulates mitochondrial respiration.•Canagliflozin impairs glutamine-mediated anaplerosis through the citric acid ...cycle.•Canagliflozin mediates antiproliferative response through inhibition of glutamine metabolism.
Notwithstanding that high rates of glucose uptake and glycolysis are common in neoplasia, pharmacological efforts to inhibit glucose utilization for cancer treatment have not been successful. Recent evidence suggests that in addition to classical glucose transporters, sodium-glucose transporters (SGLTs) are expressed by cancers. We therefore investigated the possibility that SGLT inhibitors, which are used in treatment of type 2 diabetes, may exert antineoplastic activity by limiting glucose uptake. We show that the SGLT2 inhibitor canagliflozin inhibits proliferation of breast cancer cells. Surprisingly, the antiproliferative effects of canagliflozin are not affected by glucose availability nor by the level of expression of SGLT2. Canagliflozin reduces oxygen consumption and glutamine metabolism through the citric acid cycle. The antiproliferative effects of canagliflozin are linked to inhibition of glutamine metabolism that fuels respiration, which represents a previously unanticipated mechanism of its potential antineoplastic action.
One-carbon metabolism fuels the high demand of cancer cells for nucleotides and other building blocks needed for increased proliferation. Although inhibitors of this pathway are widely used to treat ...many cancers, their global impact on anabolic and catabolic processes remains unclear. Using a combination of real-time bioenergetics assays and metabolomics approaches, we investigated the global effects of methotrexate on cellular metabolism. We show that methotrexate treatment increases the intracellular concentration of the metabolite AICAR, resulting in AMPK activation. Methotrexate-induced AMPK activation leads to decreased one-carbon metabolism gene expression and cellular proliferation as well as increased global bioenergetic capacity. The anti-proliferative and pro-respiratory effects of methotrexate are AMPK-dependent, as cells with reduced AMPK activity are less affected by methotrexate treatment. Conversely, the combination of methotrexate with the AMPK activator, phenformin, potentiates its anti-proliferative activity in cancer cells. These data highlight a reciprocal effect of methotrexate on anabolic and catabolic processes and implicate AMPK activation as a metabolic determinant of methotrexate response.
Tumor progression is associated with dedifferentiated histopathologies concomitant with cancer cell survival within a changing, and often hostile, tumor microenvironment. These processes are enabled ...by cellular plasticity, whereby intracellular cues and extracellular signals are integrated to enable rapid shifts in cancer cell phenotypes. Cancer cell plasticity, at least in part, fuels tumor heterogeneity and facilitates metastasis and drug resistance. Protein synthesis is frequently dysregulated in cancer, and emerging data suggest that translational reprograming collaborates with epigenetic and metabolic programs to effectuate phenotypic plasticity of neoplasia. Herein, we discuss the potential role of mRNA translation in cancer cell plasticity, highlight emerging histopathological correlates, and deliberate on how this is related to efforts to improve understanding of the complex tumor ecology.
Neoplastic progression is characterized by alterations in tissue architecture, such as a loss of structure–function relationships and the emergence of dedifferentiated histopathologies.To progress, metastasize, and evade therapies, cancer cells must adapt to new and unfavorable microenvironments.Cancer cell plasticity occurs concomitantly with tumor progression and can limit the effectiveness of anticancer therapies.Protein synthesis is often dysregulated in neoplasia, with translational reprogramming emerging as a central feature of adaptive plasticity.Dissecting the mechanisms of translational reprograming in response to changing tumor microenvironments holds a promise to clarify the molecular underpinnings of cancer cell plasticity and its corresponding histopathological manifestations.
Glutamine metabolism is a central metabolic pathway in cancer. Recently, reductive carboxylation of glutamine for lipogenesis has been shown to constitute a key anabolic route in cancer cells. ...However, little is known regarding central regulators of the various glutamine metabolic pathways in cancer cells.
The impact of PGC-1α and ERRα on glutamine enzyme expression was assessed in ERBB2+ breast cancer cell lines with quantitative RT-PCR, chromatin immunoprecipitation, and immunoblotting experiments. Glutamine flux was quantified using 13C-labeled glutamine and GC/MS analyses. Functional assays for lipogenesis were performed using 14C-labeled glutamine. The expression of glutamine metabolism genes in breast cancer patients was determined by bioinformatics analyses using The Cancer Genome Atlas.
We show that the transcriptional coactivator PGC-1α, along with the transcription factor ERRα, is a positive regulator of the expression of glutamine metabolism genes in ERBB2+ breast cancer. Indeed, ERBB2+ breast cancer cells with increased expression of PGC-1α display elevated expression of glutamine metabolism genes. Furthermore, ERBB2+ breast cancer cells with reduced expression of PGC-1α or when treated with C29, a pharmacological inhibitor of ERRα, exhibit diminished expression of glutamine metabolism genes. The biological relevance of the control of glutamine metabolism genes by the PGC-1α/ERRα axis is demonstrated by consequent regulation of glutamine flux through the citric acid cycle. PGC-1α and ERRα regulate both the canonical citric acid cycle (forward) and the reductive carboxylation (reverse) fluxes; the latter can be used to support de novo lipogenesis reactions, most notably in hypoxic conditions. Importantly, murine and human ERBB2+ cells lines display a significant dependence on glutamine availability for their growth. Finally, we show that PGC-1α expression is positively correlated with that of the glutamine pathway in ERBB2+ breast cancer patients, and high expression of this pathway is associated with reduced patient survival.
These data reveal that the PGC-1α/ERRα axis is a central regulator of glutamine metabolism in ERBB2+ breast cancer. This novel regulatory link, as well as the marked reduction in patient survival time associated with increased glutamine pathway gene expression, suggests that targeting glutamine metabolism may have therapeutic potential in the treatment of ERBB2+ breast cancer.
Mutations in genes encoding cytochrome c oxidase (mitochondrial complex IV) subunits and assembly factors e.g., synthesis of cytochrome c oxidase 2 (SCO2) are linked to severe metabolic syndromes. ...Notwithstanding that SCO2 is under transcriptional control of tumor suppressor p53, the role of mitochondrial complex IV dysfunction in cancer metabolism remains obscure. Herein, we demonstrate that the loss of SCO2 in HCT116 colorectal cancer cells leads to significant metabolic and signaling perturbations. Specifically, abrogation of SCO2 increased NAD+ regenerating reactions and decreased glucose oxidation through citric acid cycle while enhancing pyruvate carboxylation. This was accompanied by a reduction in amino acid levels and the accumulation of lipid droplets. In addition, SCO2 loss resulted in hyperactivation of the insulin‐like growth factor 1 receptor (IGF1R)/AKT axis with paradoxical downregulation of mTOR signaling, which was accompanied by increased AMP‐activated kinase activity. Accordingly, abrogation of SCO2 expression appears to increase the sensitivity of cells to IGF1R and AKT, but not mTOR inhibitors. Finally, the loss of SCO2 was associated with reduced proliferation and enhanced migration of HCT116 cells. Collectively, herein we describe potential adaptive signaling and metabolic perturbations triggered by mitochondrial complex IV dysfunction.
In this study, we provide evidence suggesting potential adaptive mechanisms that are activated in response to dysfunction of mitochondrial complex IV in HCT116 colon cancer cell line. These mechanisms involve dramatic metabolic reprogramming to compensate for the disruption of mitochondrial functions that is accompanied by the activation of the IGF1R/AKT axis, increased AMPK activity, and paradoxical downregulation of mTORC1 signaling.
Emerging data suggest a significant cross-talk between metabolic and epigenetic programs. However, the relationship between the mechanistic target of rapamycin (mTOR), which is a pivotal metabolic ...regulator, and epigenetic modifications remains poorly understood. Our results show that mTORC1 activation caused by the abrogation of its negative regulator tuberous sclerosis complex 2 (TSC2) coincides with increased levels of the histone modification H3K27me3 but not H3K4me3 or H3K9me3. This selective H3K27me3 induction was mediated via 4E-BP-dependent increase in EZH2 protein levels. Surprisingly, mTOR inhibition also selectively induced H3K27me3. This was independent of TSC2, and was paralleled by reduced EZH2 and increased EZH1 protein levels. Notably, the ability of mTOR inhibitors to induce H3K27me3 levels was positively correlated with their anti-proliferative effects. Collectively, our findings demonstrate that both activation and inhibition of mTOR selectively increase H3K27me3 by distinct mechanisms, whereby the induction of H3K27me3 may potentiate the anti-proliferative effects of mTOR inhibitors.
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•Paradoxically, both mTOR activation and inhibition induce H3K27me3•The effect of mTOR inhibitors on H3K27me3 is not secondary to cell-cycle arrest•H3K27me3 triggered by mTOR suppression coincides with perturbations in EZH1/2 ratio•H3K27me3 impacts the anti-proliferative effects of mTOR inhibitors
Molecular biology; Molecular mechanism of gene regulation; Epigenetics
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