Hypoxia inducible factor-1α: Its role in colorectal carcinogenesis and metastasis

Nagaraju, Ganji Purnachandra; Bramhachari, Pallaval Veera; Raghu, Godi; El‐Rayes, Bassel F.

doi:10.1016/j.canlet.2015.06.005

Cited by 104 publications

(75 citation statements)

References 134 publications

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“…Hypoxia regulates numerous genes associated with tumor vascularization, invasion, drug resistance and metastasis (reviewed in [11]). The effects of hypoxia on TRAIL-induced cell death remain to date controversial.…”

Section: Discussionmentioning

confidence: 99%

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Hypoxia regulates TRAIL sensitivity of colorectal cancer cells through mitochondrial autophagy

et al. 2016

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The capacity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to selectively induce cell death in malignant cells triggered numerous attempts for therapeutic exploitation. In clinical trials, however, TRAIL did not live up to the expectations, as tumors exhibit high rates of TRAIL resistance in vivo. Response to anti-cancer therapy is determined not only by cancer cell intrinsic factors (e.g. oncogenic mutations), but also modulated by extrinsic factors such as the hypoxic tumor microenvironment.Here, we address the effect of hypoxia on pro-apoptotic TRAIL signaling in colorectal cancer cells. We show that oxygen levels modulate susceptibility to TRAIL-induced cell death, which is severely impaired under hypoxia (0.5% O2). Mechanistically, this is attributable to hypoxia-induced mitochondrial autophagy. Loss of mitochondria under hypoxia restricts the availability of mitochondria-derived pro-apoptotic molecules such as second mitochondria-derived activator of caspase (SMAC), thereby disrupting amplification of the apoptotic signal emanating from the TRAIL death receptors and efficiently blocking cell death in type-II cells. Moreover, we identify strategies to overcome TRAIL resistance in low oxygen environments. Counteracting hypoxia-induced loss of endogenous SMAC by exogenous substitution of SMAC mimetics fully restores TRAIL sensitivity in colorectal cancer cells. Alternatively, enforcing a mitochondria-independent type-I mode of cell death by targeting the type-II phenotype gatekeeper X-linked inhibitor of apoptosis protein (XIAP) is equally effective.Together, our results indicate that tumor hypoxia impairs TRAIL efficacy but this limitation can be overcome by combining TRAIL with SMAC mimetics or XIAP-targeting drugs. Our findings may help to exploit the potential of TRAIL in cancer therapy.

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Section: Discussionmentioning

confidence: 99%

“…This transcription factor ensures cell survival through adaptive changes in cell metabolism (reviewed in [10]). Notably, HIF1α has also been implicated in carcinogenesis and metastasis of colorectal cancer [11] and overexpression is associated with poor prognosis [12]. …”

Section: Introductionmentioning

confidence: 99%

Hypoxia regulates TRAIL sensitivity of colorectal cancer cells through mitochondrial autophagy

et al. 2016

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“…HIF-1α is a central molecule involved in mediating these effects of hypoxia. In colorectal cancer, hypoxia stabilizes the transcription factor HIF-1α, leading to the expression of genes that are involved in tumor vascularization, metastasis/migration, cell survival and chemo-resistance [9, 10]. Therefore, HIF-1α is a rational target for the development of new therapeutics for colorectal cancer.…”

Section: Introductionmentioning

confidence: 99%

Zinc finger protein 91 (ZFP91) activates HIF-1α via NF-κB/p65 to promote proliferation and tumorigenesis of colon cancer

Wang

et al. 2016

Oncotarget

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Zinc finger protein 91 (ZFP91) has been reported to be involved in various biological processes. However, the clinical significance and biological role of ZFP91 in colon cancer remains unknown. Here, we show that ZFP91 expression is upregulated in patients with colon cancer. We found that ZFP91 upregulated HIF-1α at the levels of promoter and protein in colon cancer cells. Using chromatin immunoprecipitation, electrophoretic mobility shift assay and luciferase reporter gene assay, we found that NF-κB/p65 is required for the binding of ZFP91 to the HIF-1α promoter at −197/−188 base pairs and for the transcriptional activation of HIF-1α gene mediated by ZFP91. Flow cytometry, 5-ethynyl-2′-deoxyuridine (EdU) incorporation and tumor xenograft assay demonstrated that ZFP91 enhanced cell proliferation of colon cancer through upregulating HIF-1α in vitro and in vivo. Furthermore, ZFP91 is positively associated with HIF-1α in human colon cancer. Thus, we concluded that ZFP91 activates transcriptional coregulatory protein HIF-1α through transcription factor NF-κB/p65 in the promotion of proliferation and tumorigenesis in colon cancer cell. ZFP91 may serve as a driver gene to activate HIF-1α transcription in the development of cancer.

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“…Of these, alteration of metabolic pathways is regarded as a driving force of tumor initiation and progression [2,3]. Tumor cells always have a hypoxic microenvironment, and to overcome this harsh environment, cancer cells develop adaptive responses to hypoxia by activating hypoxia-inducible genes [4][5][6]. Hypoxia is a major characteristic of cancer, and in hypoxic conditions, metabolism in cancer cells is reprogrammed from oxidative phosphorylation to glycolysis [7,8].…”

Section: Introductionmentioning

confidence: 99%

PGK1 is a Potential Survival Biomarker and Invasion Promoter by Regulating the HIF-1α–Mediated Epithelial-Mesenchymal Transition Process in Breast Cancer

Wei

et al. 2018

Cell Physiol Biochem

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Background/Aims: Glycolysis, a multi-step enzymatic reaction, is considered to be the root of cancer development and progression. The aim of this study is to figure out which glycolysis enzyme participates in the progression of breast cancer and its possible mechanisms. Materials: We firstly screened out PGK1 by performing an RT-PCR array of glycolysis-related genes in three paired breast cancer samples, and further investigated PGK1 using TCGA and our own database. The effect and mechanism of PGK1 on cell invasion was further explored both in vitro and using patient samples. Results: PGK1 was most upregulated in T3N0 with distant metastases compared to those with no metastases. In the TCGA database, high PGK1 expression predicted poor overall survival (OS) in breast cancer and some other cancers (P< 0.001). In the validation cohort, high PGK1 expression was significantly correlated with larger tumor size (P=0.011) and advanced TNM stage (P=0.033), and PGK1 expression was an independent prognostic factor for OS and disease free survival (DFS) in both univariate and multivariate regression analyses (P< 0.05). Functional studies indicated that knockdown of PGK1 expression significantly inhibited invasion and reversed the epithelial-mesenchymal transition process in breast cancer cells (P< 0.05). Mechanistically, PGK1 increased HRE luciferase activity in a dose-dependent manner, while silencing PGK1 expression decreased HRE activity. Conclusion: High PGK1 expression was associated with poor prognosis in breast cancer, because PGK1 and HIF-1α formed a positive feed-forward loop and thus stimulated breast cancer progression and metastases. Based on these results, PGK1 may serve as a promising biomarker and target therapy for breast cancer.

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Hypoxia inducible factor-1α: Its role in colorectal carcinogenesis and metastasis

Cited by 104 publications

References 134 publications

Hypoxia regulates TRAIL sensitivity of colorectal cancer cells through mitochondrial autophagy

Hypoxia regulates TRAIL sensitivity of colorectal cancer cells through mitochondrial autophagy

Zinc finger protein 91 (ZFP91) activates HIF-1α via NF-κB/p65 to promote proliferation and tumorigenesis of colon cancer

PGK1 is a Potential Survival Biomarker and Invasion Promoter by Regulating the HIF-1α–Mediated Epithelial-Mesenchymal Transition Process in Breast Cancer

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