TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Cancer Progression ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Human Lung Cancer ◽  
Regulatory Subunit ◽  
Patients With Cancer ◽  
Hypoxia Inducible Factor 1 ◽  
Chemically Induced ◽  
Induced Tumors ◽  
Patient Prognosis

Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activationare associated with cancer progression. Here, we demonstrate thatthe transcription factor TAp73 opposes HIF-1 activity through anontranscriptional mechanism, thus affecting tumor angiogenesis.TAp73-deficient mice have an increased incidence of spontaneousand chemically induced tumors that also display enhanced vascularization.Mechanistically, TAp73 interacts with the regulatory subunit(α) of HIF-1 and recruits mouse double minute 2 homolog intothe protein complex, thus promoting HIF-1α polyubiquitination andconsequent proteasomal degradation in an oxygen-independentmanner. In human lung cancer datasets, TAp73 strongly predictsgood patient prognosis, and its expression is associated with lowHIF-1 activation and angiogenesis. Our findings, supported by invivo and clinical evidence, demonstrate a mechanism for oxygenindependentHIF-1 regulation, which has important implicationsfor individualizing therapies in patients with cancer.

scholarly journals TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

2014 ◽  
Vol 112 (1) ◽  
pp. 226-231 ◽  
Author(s):  
Ivano Amelio ◽  
Satoshi Inoue ◽  
Elke K. Markert ◽  
Arnold J. Levine ◽  
Richard A. Knight ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Tumor Angiogenesis ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Human Lung Cancer ◽  
Regulatory Subunit ◽  
Independent Manner ◽  
Induced Tumors ◽  
Patient Prognosis

Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activation are associated with cancer progression. Here, we demonstrate that the transcription factor TAp73 opposes HIF-1 activity through a nontranscriptional mechanism, thus affecting tumor angiogenesis. TAp73-deficient mice have an increased incidence of spontaneous and chemically induced tumors that also display enhanced vascularization. Mechanistically, TAp73 interacts with the regulatory subunit (α) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1α polyubiquitination and consequent proteasomal degradation in an oxygen-independent manner. In human lung cancer datasets, TAp73 strongly predicts good patient prognosis, and its expression is associated with low HIF-1 activation and angiogenesis. Our findings, supported by in vivo and clinical evidence, demonstrate a mechanism for oxygen-independent HIF-1 regulation, which has important implications for individualizing therapies in patients with cancer.

scholarly journals From tumor hypoxia to cancer progression: the implications of hypoxia-inducible factor-1 expression in cancers

2012 ◽  
Vol 45 (2) ◽  
pp. 73 ◽  
Author(s):  
Fariz Nurwidya ◽  
Fumiyuki Takahashi ◽  
Kunihiko Minakata ◽  
Akiko Murakami ◽  
Kazuhisa Takahashi
Keyword(s):  
Cancer Progression ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Hypoxia Inducible Factor 1

Anticancer Activity of Natural Flavonoids: Inhibition of HIF-1α Signaling Pathway

2020 ◽  
Vol 23 (26) ◽  
pp. 2945-2959 ◽  
Author(s):  
Xiangping Deng ◽  
Yijiao Peng ◽  
Jingduo Zhao ◽  
Xiaoyong Lei ◽  
Xing Zheng ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Secondary Metabolites ◽  
Anticancer Agents ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Pharmacological Activities ◽  
Hypoxia Inducible Factor 1 ◽  
The Past ◽  
Low Toxicity ◽  
Tumor Blood Vessels

Rapid tumor growth is dependent on the capability of tumor blood vessels and glycolysis to provide oxygen and nutrients. Tumor hypoxia is a common characteristic of many solid tumors, and it essentially happens when the growth of the tumor exceeds the concomitant angiogenesis. Hypoxia-inducible factor 1 (HIF-1) as the critical transcription factor in hypoxia regulation is activated to adapt to this hypoxia situation. Flavonoids, widely distributed in plants, comprise many polyphenolic secondary metabolites, possessing broadspectrum pharmacological activities, including their potentiality as anticancer agents. Due to their low toxicity, intense efforts have been made for investigating natural flavonoids and their derivatives that can be used as HIF-1α inhibitors for cancer therapy during the past few decades. In this review, we sum up the findings concerning the inhibition of HIF-1α by natural flavonoids in the last few years and propose the idea of designing tumor vascular and glycolytic multi-target inhibitors with HIF-1α as one of the targets.

Abstract B7: Hypoxia-inducible factor 1 mediates thrombosis-associated cancer progression

2013 ◽  
Author(s):  
Colin E. Evans ◽  
Cristina Branco-Price ◽  
Julia Humphries ◽  
Ashar Wadoodi ◽  
Prakash Saha ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1

LncIHAT is induced by hypoxia-inducible factor 1 and promotes breast cancer progression

2020 ◽  
pp. molcanres.0383.2020
Author(s):  
Lin Chen ◽  
Lei Bao ◽  
Yanling Niu ◽  
Jennifer E. Wang ◽  
Ashwani Kumar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Hypoxia Inducible Factor ◽  
Breast Cancer Progression ◽  
Hypoxia Inducible Factor 1

scholarly journals Microenvironment and Radiation Therapy

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Michio Yoshimura ◽  
Satoshi Itasaka ◽  
Hiroshi Harada ◽  
Masahiro Hiraoka
Keyword(s):  
Radiation Therapy ◽  
Tumor Microenvironment ◽  
Antiangiogenic Therapy ◽  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Tumor Oxygenation ◽  
Therapeutic Effects ◽  
Antitumor Effects ◽  
Hypoxia Inducible Factor 1 ◽  
Effects Of Radiation

Dependency on tumor oxygenation is one of the major features of radiation therapy and this has led many radiation biologists and oncologists to focus on tumor hypoxia. The first approach to overcome tumor hypoxia was to improve tumor oxygenation by increasing oxygen delivery and a subsequent approach was the use of radiosensitizers in combination with radiation therapy. Clinical use of some of these approaches was promising, but they are not widely used due to several limitations. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that is activated by hypoxia and induces the expression of various genes related to the adaptation of cellular metabolism to hypoxia, invasion and metastasis of cancer cells and angiogenesis, and so forth. HIF-1 is a potent target to enhance the therapeutic effects of radiation therapy. Another approach is antiangiogenic therapy. The combination with radiation therapy is promising, but several factors including surrogate markers, timing and duration, and so forth have to be optimized before introducing it into clinics. In this review, we examined how the tumor microenvironment influences the effects of radiation and how we can enhance the antitumor effects of radiation therapy by modifying the tumor microenvironment.

Role of hypoxia-inducible factor-1α as a cancer therapy target

2006 ◽  
Vol 13 (Supplement_1) ◽  
pp. S61-S75 ◽  
Author(s):  
Shalini Patiar ◽  
Adrian L Harris
Keyword(s):  
Anticancer Agents ◽  
Ph Regulation ◽  
Hypoxia Inducible Factor ◽  
Genetic Alterations ◽  
Solid Tumours ◽  
Tumour Suppressor Genes ◽  
Hypoxia Inducible Factor 1 ◽  
And Migration ◽  
Patient Prognosis ◽  
Therapy Target

Hypoxia occurs in solid tumours due to a mismatch between tumour growth and angiogenesis. Hypoxia in solid tumours is associated with an aggressive phenotype and resistance to radiation therapy and chemotherapy leading to poor patient prognosis. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor, which is activated in response to intratumoural hypoxia and as a result of genetic alterations that activate oncogenes and inactivate tumour suppressor genes. It plays a key role in the adaptation of tumour cells to hypoxia by activating the transcription of genes, which regulate several biological processes including angiogenesis, cell proliferation and survival, glucose metabolism, pH regulation and migration. This makes HIF-1 an attractive target for the development of anticancer agents. The success of these agents depends on reliable methods to identify those patients most likely to benefit from HIF-1-targeted therapy. Several novel small molecule inhibitors of HIF-1 have been identified and are moving towards clinical trials, but none of these are specific for HIF-1. Further work is ongoing to identify more selective HIF-1 inhibitors.

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