Cancer cells are known to undergo metabolic reprogramming to sustain survival and rapid proliferation, however, it remains to be fully elucidated how oncogenic lesions coordinate the metabolic switch under various stressed conditions. Here we show that deprivation of glucose or glutamine, two major nutrition sources for cancer cells, dramatically activated serine biosynthesis pathway (SSP) that was accompanied by elevated cMyc expression. We further identified that cMyc stimulated SSP activation by transcriptionally upregulating expression of multiple SSP enzymes. Moreover, we demonstrated that SSP activation facilitated by cMyc led to elevated glutathione (GSH) production, cell cycle progression and nucleic acid synthesis, which are essential for cell survival and proliferation especially under nutrient-deprived conditions. We further uncovered that phosphoserine phosphatase (PSPH), the final rate-limiting enzyme of the SSP pathway, is critical for cMyc-driven cancer progression both in vitro and in vivo, and importantly, aberrant expression of PSPH is highly correlated with mortality in hepatocellular carcinoma (HCC) patients, suggesting a potential causal relation between this cMyc-regulated enzyme, or SSP activation in general, and cancer development. Taken together, our results reveal that aberrant expression of cMyc leads to the enhanced SSP activation, an essential part of metabolic switch, to facilitate cancer progression under nutrient-deprived conditions.
LKB1 loss-of-function mutations, observed in ∼30% of human lung adenocarcinomas, contribute significantly to lung cancer malignancy progression. We show that lysyl oxidase (LOX), negatively regulated by LKB1 through mTOR-HIF-1α signaling axis, mediates lung cancer progression. Inhibition of LOX activity dramatically alleviates lung cancer malignancy progression. Up-regulated LOX expression triggers excess collagen deposition in Lkb1-deficient lung tumors, and thereafter results in enhanced cancer cell proliferation and invasiveness through activation of β1 integrin signaling. High LOX level and activity correlate with poor prognosis and metastasis. Our findings provide evidence of how LKB1 loss of function promotes lung cancer malignancy through remodeling of extracellular matrix microenvironment, and identify LOX as a potential target for disease treatment in lung cancer patients.T he high mortality of lung cancer (1) is largely attributable to failure of early diagnosis and metastasis frequently observed at the time of diagnosis. Tumor suppressor loss of function is widely adopted in tumor initiation and progression. The roles of LKB1 as a tumor suppressor have emerged from the observation of increased risk of malignancy in gastrointestinal tract in PeutzJeghers syndrome (PJS) patients harboring germ-line LKB1 mutations (2, 3). Although rare in most types of human cancers (4, 5), LKB1 loss-of-function somatic mutations are frequently observed in human non-small-cell lung cancer (NSCLC) (6-10). Mice with oncogenic Kras G12D mutant develop lung tumors with long latency and low aggressiveness. Concomitant loss of Lkb1 significantly shortened the latency, increased tumor burden, and promoted lung cancer invasion and distant metastasis, comparable to that from p53 loss (6). Yet, the molecular mechanisms involved remain largely unknown.Cancer progression is a reciprocal process involving intimate interaction between tumor cells and tumor stroma, including extracellular matrix (ECM). ECM alteration and remodeling is one of the most frequently observed and most important events during malignancy progression, which subsequently modulates cell-matrix and cell-cell interaction and results in altered cell behavior (11). Increasing interests and efforts have been paid to those enzymes involved in ECM remodeling, among which lysyl oxidase (LOX) is of particular interest. LOX oxidizes lysine residues in collagen and elastin, resulting in covalent cross-linking and stabilization of these ECM structural components (12). Aberrant LOX expression or enzymatic activity has been linked to a variety of pathological conditions, including breast cancer and lung cancer (13)(14)(15)(16). LOX is associated with hypoxia in human breast cancer and head and neck tumors, and is responsible for hypoxiainduced tumor metastasis (13). Although studies have implicated deregulated LOX mRNA and protein levels in lung adenocarcinomas (17, 18), the roles and molecular mechanisms of LOX involved in lung cancer progression are poorly understood.Here we...
Aberrant expression of Lin28 and let-7 has been observed in many human malignancies. However, its functions and underlying mechanisms remain largely elusive. Here we show that aberrant expression of Lin28 and let-7 facilitates aerobic glycolysis, or Warburg effect, in cancer cells. Mechanistically, we discover that Lin28A and Lin28B enhance, whereas let-7 suppresses, aerobic glycolysis via targeting pyruvate dehydrogenase kinase 1, or PDK1, in a hypoxia-or hypoxia-inducible factor-1 (HIF-1)-independent manner, illustrating a novel pathway to mediate aerobic glycolysis of cancer cells even in ambient oxygen levels. Importantly, we further demonstrate that PDK1 is critical for Lin28A-and Lin28B-mediated cancer proliferation both in vitro and in vivo, establishing a previously unappreciated mechanism by which Lin28/let-7 axis facilitates Warburg effect to promote cancer progression. Our findings suggest a potential rationale to target PDK1 for cancer therapy in malignancies with aberrant expression of Lin28 and let-7.
Cancer cells are known for their capacity to rewire metabolic pathways to support survival and proliferation under various stress conditions. Ketone bodies, though produced in the liver, are not consumed in normal adult liver cells. We find here that ketone catabolism or ketolysis is re-activated in hepatocellular carcinoma (HCC) cells under nutrition deprivation conditions. Mechanistically, 3-oxoacid CoA-transferase 1 (OXCT1), a rate-limiting ketolytic enzyme whose expression is suppressed in normal adult liver tissues, is re-induced by serum starvation-triggered mTORC2-AKT-SP1 signaling in HCC cells. Moreover, we observe that enhanced ketolysis in HCC is critical for repression of AMPK activation and protects HCC cells from excessive autophagy, thereby enhancing tumor growth. Importantly, analysis of clinical HCC samples reveals that increased OXCT1 expression predicts higher patient mortality. Taken together, we uncover here a novel metabolic adaptation by which nutrition-deprived HCC cells employ ketone bodies for energy supply and cancer progression.
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