Browsing by Author "Yang, Lifeng"

Now showing 1 - 6 of 6
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    Amplification of USP13 drives ovarian cancer metabolism
    (Springer Nature, 2016) Han, Cecil; Yang, Lifeng; Choi, Hyun Ho; Baddour, Joelle; Achreja, Abhinav; Liu, Yunhua; Li, Yujing; Li, Jiada; Wan, Guohui; Huang, Cheng; Ji, Guang; Zhang, Xinna; Nagrath, Deepak; Lu, Xiongbin; Bioengineering; Chemical and Biomolecular Engineering
    Dysregulated energetic metabolism has been recently identified as a hallmark of cancer. Although mutations in metabolic enzymes hardwire metabolism to tumourigenesis, they are relatively infrequent in ovarian cancer. More often, cancer metabolism is re-engineered by altered abundance and activity of the metabolic enzymes. Here we identify ubiquitin-specific peptidase 13 (USP13) as a master regulator that drives ovarian cancer metabolism. USP13 specifically deubiquitinates and thus upregulates ATP citrate lyase and oxoglutarate dehydrogenase, two key enzymes that determine mitochondrial respiration, glutaminolysis and fatty acid synthesis. The USP13 gene is co-amplified with PIK3CA in 29.3% of high-grade serous ovarian cancers and its overexpression is significantly associated with poor clinical outcome. Inhibiting USP13 remarkably suppresses ovarian tumour progression and sensitizes tumour cells to the treatment of PI3K/AKT inhibitor. Our results reveal an important metabolism-centric role of USP13, which may lead to potential therapeutics targeting USP13 in ovarian cancers.
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    Glutaminolysis: A Hallmark of Cancer Metabolism
    (2016-04-15) Yang, Lifeng; Nagrath, Deepak
    The goals of these projects are to study the critical role of glutamine (Gln) in ovarian cancer growth, metastasis, drug resistance and sources of glutamine in tumor microenvironment. 1): Gln‐addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. 1): we have uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low‐invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high‐invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients’ microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the activation of STAT3, a mediator of signaling pathways which regulates cancer hallmarks in invasive OVCA cells. Our findings suggest that a combined approach of targeting high‐invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting low‐invasive OVCA cells by inhibiting glutamine synthesis and STAT3 may lead to potential therapeutic approaches for treating OVCAs. 2): Reactive stromal cells are an integral part of tumor microenvironment (TME) in tumors and interact with cancer cells to regulate their growth and survival. Although targeting stromal cells could be a viable therapy to regulate the communication between TME and cancer cells, identification of stromal targets which make cancer cells vulnerable has remained challenging and still elusive. Here, we identify a previously unrecognized mechanism whereby metabolism of reactive stromal cells is reprogrammed through upregulated glutamine anabolic pathway. This dysfunctional stromal metabolism confers atypical metabolic flexibility and adaptive mechanisms in stromal cells allowing them to harness carbon and nitrogen from noncanonical sources to synthesize glutamine in nutrient-deprived conditions existing in TME. We demonstrate that targeting cancer associated fibroblasts (CAFs), a major component of reactive stroma that expresses high glutamine synthetase (GLUL), disrupts metabolic crosstalk between stromal and cancer cells. Our work underscores reliance of cancer cells on CAFs and presents a synthetic lethal approach to target tumor stroma and cancer cells simultaneously for desirable therapeutic outcomes.
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    HSulf-1 deficiency dictates a metabolic reprograming of glycolysis and TCA cycle in ovarian cancer
    (Impact Journals, LLC., 2015) Mondal, Susmita; Roy, Debarshi; Camacho-Pereira, Juliana; Khurana, Ashwani; Chini, Eduardo; Yang, Lifeng; Baddour, Joelle; Stilles, Katherine; Padmabandu, Seth; Leung, Sam; Kalloger, Steve; Gilks, Blake; Lowe, Val; Dierks, Thomas; Hammond, Edward; Dredge, Keith; Nagrath, Deepak; Shridhar, Viji
    Warburg effect has emerged as a potential hallmark of many cancers. However, the molecular mechanisms that led to this metabolic state of aerobic glycolysis, particularly in ovarian cancer (OVCA) have not been completely elucidated. HSulf-1 predominantly functions by limiting the bioavailability of heparan binding growth factors and hence their downstream signaling. Here we report that HSulf-1, a known putative tumor suppressor, is a negative regulator of glycolysis. Silencing of HSulf-1 expression in OV202 cell line increased glucose uptake and lactate production by upregulating glycolytic genes such as Glut1, HKII, LDHA, as well as metabolites. Conversely, HSulf-1 overexpression in TOV21G cells resulted in the down regulation of glycolytic enzymes and reduced glycolytic phenotype, supporting the role of HSulf-1 loss in enhanced aerobic glycolysis. HSulf-1 deficiency mediated glycolytic enhancement also resulted in increased inhibitory phosphorylation of pyruvate dehydrogenase (PDH) thus blocking the entry of glucose flux into TCA cycle. Consistent with this, metabolomic and isotope tracer analysis showed reduced glucose flux into TCA cycle. Moreover, HSulf-1 loss is associated with lower oxygen consumption rate (OCR) and impaired mitochondrial function. Mechanistically, lack of HSulf-1 promotes c-Myc induction through HB-EGF-mediated p-ERK activation. Pharmacological inhibition of c-Myc reduced HB-EGF induced glycolytic enzymes implicating a major role of c-Myc in loss of HSulf-1 mediated altered glycolytic pathway in OVCA. Similarly, PG545 treatment, an agent that binds to heparan binding growth factors and sequesters growth factors away from their ligand also blocked HB-EGF signaling and reduced glucose uptake in vivo in HSulf-1 deficient cells.
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    Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer
    (EMBO, 2014) Yang, Lifeng; Moss, Tyler; Mangala, Lingegowda S.; Marini, Juan; Zhao, Hongyun; Wahlig, Stephen; Armaiz-Pena, Guillermo; Jiang, Dahai; Achreja, Abhinav; Win, Julia; Roopaimoole, Rajesha; Rodriguez-Aguayo, Cristian; Mercado-Uribe, Imelda; Lopez-Berestein, Gabriel; Liu, Jinsong; Tsukamoto, Takashi; Sood, Anil K.; Ram, Prahlad T.; Nagrath, Deepak; Bioengineering; Chemical and Biomolecular Engineering
    Glutamine can play a critical role in cellular growth in multiple cancers. Glutamine‐addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. Here, we have uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low‐invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high‐invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients’ microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the activation of STAT3, a mediator of signaling pathways which regulates cancer hallmarks in invasive OVCA cells. Our findings suggest that a combined approach of targeting high‐invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting low‐invasive OVCA cells by inhibiting glutamine synthesis and STAT3 may lead to potential therapeutic approaches for treating OVCAs.
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    Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal adenocarcinoma
    (Springer Nature, 2017) Ju, Huai-Qiang; Ying, Haoqiang; Tian, Tian; Ling, Jianhua; Fu, Jie; Lu, Yu; Wu, Min; Yang, Lifeng; Achreja, Abhinav; Chen, Gang; Zhuang, Zhuonan; Wang, Huamin; Nagrath, Deepak; Yao, Jun; Hung, Mien-Chie; DePinho, Ronald A.; Huang, Peng; Xu, Rui-Hua; Chiao, Paul J.; Laboratory for Systems Biology of Human Diseases
    Kras activation and p16 inactivation are required to develop pancreatic ductal adenocarcinoma (PDAC). However, the biochemical mechanisms underlying these double alterations remain unclear. Here we discover that NAD(P)H oxidase 4 (NOX4), an enzyme known to catalyse the oxidation of NAD(P)H, is upregulated when p16 is inactivated by looking at gene expression profiling studies. Activation of NOX4 requires catalytic subunit p22phox, which is upregulated following Kras activation. Both alterations are also detectable in PDAC cell lines and patient specimens. Furthermore, we show that elevated NOX4 activity accelerates oxidation of NADH and supports increased glycolysis by generating NAD+, a substrate for GAPDH-mediated glycolytic reaction, promoting PDAC cell growth. Mechanistically, NOX4 was induced through p16-Rb-regulated E2F and p22phox was induced by KrasG12V-activated NF-κB. In conclusion, we provide a biochemical explanation for the cooperation between p16 inactivation and Kras activation in PDAC development and suggest that NOX4 is a potential therapeutic target for PDAC.
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    Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism
    (eLife Sciences Publications Ltd., 2016) Zhao, Hongyun; Yang, Lifeng; Baddour, Joelle; Achreja, Abhinav; Bernard, Vincent; Moss, Tyler; Marini, Juan C.; Tudawe, Thavisha; Seviour, Elena G.; San Lucas, F. Anthony; Alvarez, Hector; Gupta, Sonal; Maiti, Sourindra N.; Cooper, Laurence; Peehl, Donna; Ram, Prahlad T.; Maitra, Anirban; Nagrath, Deepak; Bioengineering; Chemical and Biomolecular Engineering; Laboratory for Systems Biology of Human Diseases
    Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate that exosomes secreted by patient-derived CAFs can strikingly reprogram the metabolic machinery following their uptake by cancer cells. We find that CAF-derived exosomes (CDEs) inhibit mitochondrial oxidative phosphorylation, thereby increasing glycolysis and glutamine-dependent reductive carboxylation in cancer cells. Through 13C-labeled isotope labeling experiments we elucidate that exosomes supply amino acids to nutrient-deprived cancer cells in a mechanism similar to macropinocytosis, albeit without the previously described dependence on oncogenic-Kras signaling. Using intra-exosomal metabolomics, we provide compelling evidence that CDEs contain intact metabolites, including amino acids, lipids, and TCA-cycle intermediates that are avidly utilized by cancer cells for central carbon metabolism and promoting tumor growth under nutrient deprivation or nutrient stressed conditions.