Metabolic profiling reveals potential metabolic markers associated with Hypoxia Inducible Factor-mediated signalling in hypoxic cancer cells

Hypoxia or low oxygen concentration in tumor microenvironment has widespread effects ranging from altered angiogenesis and lymphangiogenesis, tumor metabolism, growth, and therapeutic resistance in different cancer types. A large number of these effects are mediated by the transcription factor hypoxia inducible factor 1⍺ (HIF-1⍺) which is activated by hypoxia. HIF1⍺ induces glycolytic genes and reduces mitochondrial respiration rate in hypoxic tumoral regions through modulation of various cells in tumor microenvironment like cancer-associated fibroblasts. Immune evasion driven by HIF-1⍺ further contributes to enhanced survival of cancer cells. By altering drug target expression, metabolic regulation, and oxygen consumption, hypoxia leads to enhanced growth and survival of cancer cells. Tumor cells in hypoxic conditions thus attain aggressive phenotypes and become resistant to chemo- and radio- therapies resulting in higher mortality. While a number of new therapeutic strategies have succeeded in targeting hypoxia, a significant improvement of these needs a more detailed understanding of the various effects and molecular mechanisms regulated by hypoxia and its effects on modulation of the tumor vasculature. This review focuses on the chief hypoxia-driven molecular mechanisms and their impact on therapeutic resistance in tumors that drive an aggressive phenotype. Impact statement Hypoxia contributes to tumor aggressiveness and promotes growth of many solid tumors that are often resistant to conventional therapies. In order to achieve successful therapeutic strategies targeting different cancer types, it is necessary to understand the molecular mechanisms and signaling pathways that are induced by hypoxia. Aberrant tumor vasculature and alterations in cellular metabolism and drug resistance due to hypoxia further confound this problem. This review focuses on the implications of hypoxia in an inflammatory TME and its impact on the signaling and metabolic pathways regulating growth and progression of cancer, along with changes in lymphangiogenic and angiogenic mechanisms. Finally, the overarching role of hypoxia in mediating therapeutic resistance in cancers is discussed.

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Re: Steroid Receptor Coactivator-3 Regulates Glucose Metabolism in Bladder Cancer Cells through Coactivation of Hypoxia Inducible Factor 1α

The Journal of Urology ◽

10.1016/j.juro.2014.09.027 ◽

2014 ◽

Vol 192 (6) ◽

pp. 1885-1885

Author(s):

Anthony Atala

Keyword(s):

Bladder Cancer ◽

Glucose Metabolism ◽

Cancer Cells ◽

Hypoxia Inducible Factor ◽

Steroid Receptor ◽

Hypoxia Inducible Factor 1Α ◽

Steroid Receptor Coactivator ◽

Bladder Cancer Cells

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mTOR Signal and Hypoxia-Inducible Factor-1α Regulate CD133 Expression in Cancer Cells

Cancer Research ◽

10.1158/0008-5472.can-09-1289 ◽

2009 ◽

Vol 69 (18) ◽

pp. 7160-7164 ◽

Cited By ~ 92

Author(s):

Kazuko Matsumoto ◽

Tokuzo Arao ◽

Kaoru Tanaka ◽

Hiroyasu Kaneda ◽

Kanae Kudo ◽

...

Keyword(s):

Cancer Cells ◽

Hypoxia Inducible Factor ◽

Cd133 Expression ◽

Hypoxia Inducible Factor 1Α

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Mass Spectrometry-Based Metabolic Profiling of Gemcitabine-Sensitive and Gemcitabine-Resistant Pancreatic Cancer Cells

Pancreas ◽

10.1097/mpa.0000000000000092 ◽

2014 ◽

Vol 43 (2) ◽

pp. 311-318 ◽

Cited By ~ 10

Author(s):

Yoshinori Fujimura ◽

Naoki Ikenaga ◽

Kenoki Ohuchida ◽

Daiki Setoyama ◽

Miho Irie ◽

...

Keyword(s):

Mass Spectrometry ◽

Pancreatic Cancer ◽

Cancer Cells ◽

Metabolic Profiling ◽

Pancreatic Cancer Cells

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Hypoxia-inducible factor 1 alpha promotes cancer stem cells-like properties in human ovarian cancer cells by upregulating SIRT1 expression

Scientific Reports ◽

10.1038/s41598-017-09244-8 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 37

Author(s):

Jie Qin ◽

Yan Liu ◽

Yongkui Lu ◽

Meiling Liu ◽

Manli Li ◽

...

Keyword(s):

Ovarian Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Hypoxia Inducible Factor ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Sirt1 Expression ◽

Hypoxia Inducible Factor 1

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Activation of Peroxisome Proliferator-activated Receptor α (PPARα) Suppresses Hypoxia-inducible Factor-1α (HIF-1α) Signaling in Cancer Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m112.367367 ◽

2012 ◽

Vol 287 (42) ◽

pp. 35161-35169 ◽

Cited By ~ 43

Author(s):

Jundong Zhou ◽

Shuyu Zhang ◽

Jing Xue ◽

Jori Avery ◽

Jinchang Wu ◽

...

Keyword(s):

Cancer Cells ◽

Hypoxia Inducible Factor ◽

Proteasome Inhibitors ◽

Tube Formation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Hypoxia Inducible Factor 1Α ◽

Anticancer Properties ◽

Pparγ Agonist ◽

Expression And Activity

Activation of peroxisome proliferator-activated receptor α (PPARα) has been demonstrated to inhibit tumor growth and angiogenesis, yet the mechanisms behind these actions remain to be characterized. In this study, we examined the effects of PPARα activation on the hypoxia-inducible factor-1α (HIF-1α) signaling pathway in human breast (MCF-7) and ovarian (A2780) cancer cells under hypoxia. Incubation of cancer cells under 1% oxygen for 16 h significantly induced HIF-1α expression and activity as assayed by Western blotting and reporter gene analysis. Treatment of the cells with PPARα agonists, but not a PPARγ agonist, prior to hypoxia diminished hypoxia-induced HIF-1α expression and activity, and addition of a PPARα antagonist attenuated the suppression of HIF-1α signaling. Activation of PPARα attenuated hypoxia-induced HA-tagged HIF-1α protein expression without affecting the HA-tagged HIF-1α mutant protein level, indicating that PPARα activation promotes HIF-1α degradation in these cells. This was further confirmed using proteasome inhibitors, which reversed PPARα-mediated suppression of HIF-1α expression under hypoxia. Using the co-immunoprecipitation technique, we found that activation of PPARα enhances the binding of HIF-1α to von Hippel-Lindau tumor suppressor (pVHL), a protein known to mediate HIF-1α degradation through the ubiquitin-proteasome pathway. Following PPARα-mediated suppression of HIF-1α signaling, VEGF secretion from the cancer cells was significantly reduced, and tube formation by endothelial cells was dramatically impaired. Taken together, these findings demonstrate for the first time that activation of PPARα suppresses hypoxia-induced HIF-1α signaling in cancer cells, providing novel insight into the anticancer properties of PPARα agonists.

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HER2 (neu) Signaling Increases the Rate of Hypoxia-Inducible Factor 1α (HIF-1α) Synthesis: Novel Mechanism for HIF-1-Mediated Vascular Endothelial Growth Factor Expression

Molecular and Cellular Biology ◽

10.1128/mcb.21.12.3995-4004.2001 ◽

2001 ◽

Vol 21 (12) ◽

pp. 3995-4004 ◽

Cited By ~ 873

Author(s):

Erik Laughner ◽

Panthea Taghavi ◽

Kelly Chiles ◽

Patrick C. Mahon ◽

Gregg L. Semenza

Keyword(s):

Breast Cancer ◽

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Cancer Cells ◽

Half Life ◽

Hypoxia Inducible Factor ◽

Dependent Manner ◽

Vascular Endothelial ◽

Her2 Signaling ◽

Endothelial Growth Factor

ABSTRACT Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator composed of HIF-1α and HIF-1β subunits. Several dozen HIF-1 targets are known, including the gene encoding vascular endothelial growth factor (VEGF). Under hypoxic conditions, HIF-1α expression increases as a result of decreased ubiquitination and degradation. The tumor suppressors VHL (von Hippel-Lindau protein) and p53 target HIF-1α for ubiquitination such that their inactivation in tumor cells increases the half-life of HIF-1α. Increased phosphatidylinositol 3-kinase (PI3K) and AKT or decreased PTEN activity in prostate cancer cells also increases HIF-1α expression by an undefined mechanism. In breast cancer, increased activity of the HER2 (also known as neu) receptor tyrosine kinase is associated with increased tumor grade, chemotherapy resistance, and decreased patient survival. HER2 has also been implicated as an inducer of VEGF expression. Here we demonstrate that HER2 signaling induced by overexpression in mouse 3T3 cells or heregulin stimulation of human MCF-7 breast cancer cells results in increased HIF-1α protein and VEGF mRNA expression that is dependent upon activity of PI3K, AKT (also known as protein kinase B), and the downstream kinase FRAP (FKBP-rapamycin-associated protein). In contrast to other inducers of HIF-1 expression, heregulin stimulation does not affect the half-life of HIF-1α but instead stimulates HIF-1α synthesis in a rapamycin-dependent manner. The 5′-untranslated region of HIF-1α mRNA directs heregulin-inducible expression of a heterologous protein. These data provide a molecular basis for VEGF induction and tumor angiogenesis by heregulin-HER2 signaling and establish a novel mechanism for the regulation of HIF-1α expression.

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Metabolic Roles of Androgen Receptor and Tip60 in Androgen-Dependent Prostate Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21186622 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6622

Author(s):

Kah Ni Tan ◽

Vicky M. Avery ◽

Catalina Carrasco-Pozo

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Cell Fate ◽

Tricarboxylic Acid Cycle ◽

Mammalian Target Of Rapamycin ◽

Hypoxia Inducible Factor ◽

Normal Prostate ◽

Calcium Calmodulin Dependent ◽

Metabolic Regulators

Androgen receptor (AR)-mediated signaling is essential for the growth and differentiation of the normal prostate and is the primary target for androgen deprivation therapy in prostate cancer. Tat interactive protein 60 kDa (Tip60) is a histone acetyltransferase that is critical for AR activation. It is well known that cancer cells rewire their metabolic pathways in order to sustain aberrant proliferation. Growing evidence demonstrates that the AR and Tip60 modulate key metabolic processes to promote the survival of prostate cancer cells, in addition to their classical roles. AR activation enhances glucose metabolism, including glycolysis, tricarboxylic acid cycle and oxidative phosphorylation, as well as lipid metabolism in prostate cancer. The AR also interacts with other metabolic regulators, including calcium/calmodulin-dependent kinase kinase 2 and mammalian target of rapamycin. Several studies have revealed the roles of Tip60 in determining cell fate indirectly by modulating metabolic regulators, such as c-Myc, hypoxia inducible factor 1α (HIF-1α) and p53 in various cancer types. Furthermore, Tip60 has been shown to regulate the activity of key enzymes in gluconeogenesis and glycolysis directly through acetylation. Overall, both the AR and Tip60 are master metabolic regulators that mediate cellular energy metabolism in prostate cancer, providing a framework for the development of novel therapeutic targets in androgen-dependent prostate cancer.

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