HIF-1 regulation: not so easy come, easy go

Koh, Mei Yee; Spivak-Kroizman, Taly R.; Powis, Garth

doi:10.1016/j.tibs.2008.08.002

Cited by 305 publications

(296 citation statements)

References 82 publications

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“…In the nucleus, the HIF-1amolecules heterodimerize with HIF-1bsubunits to bind to specific hypoxia response elements in target genes and regulate transcription. 27 We found that hypoxia-induced p-ERK1/2 increases nuclear accumulation of HIF-1a, which in turn promotes ABCG 2 mRNA and protein expression. Activation of HIF-1a leads to increased translocation of ABCG 2 from the cytoplasm to the cell member under conditions of hypoxia.…”

Section: Discussionmentioning

confidence: 70%

Hypoxia regulates ABCG₂activity through the activivation of ERK1/2/HIF-1α and contributes to chemoresistance in pancreatic cancer cells

Wang

Wei

et al. 2016

Cancer Biology & Therapy

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Pancreatic cancer is a drug resistant hypovascular tumor. Although there are many studies on the mechanism of chemoresistance in pancreatic cancers, studies on the relationship between ABCG2 and chemoresistance during hypoxia of pancreatic cancer are rare. Hypoxia-inducible factor-1 (HIF-1a) is a master regulator of the transcriptional response to oxygen deprivation in cancer cells. The aim of this study was to examine the role of ABCG 2 and HIF-1a in mediating chemoresistance during hypoxia in pancreatic cancer. In this study, we detected the expression levels of ABCG 2 , ERK/phosphorylated-ERK (p-ERK) and HIF-1a by immunohistochemistry in fresh pancreatic cancer and paracarcinoma tissues obtained from 25 patients. The mechanism by which p-ERK1/2 and HIF-1a affect ABCG 2 s expression was analyzed in the hypoxic cultured human pancreatic cancer cell line Capan-2. ABCG2-mediatedregulation of gemcitabine response under hypoxic conditions in pancreatic cancer cells was observed. It was found that ABCG 2 , ERK/p-ERK and HIF-1a were overexpressed in cancer tissues. ABCG2, HIF-1a and p-ERK levels were demonstrated to be high during hypoxic conditions in pancreatic cancer cells. Hypoxia induced phosphorylation of ERK1/2 to activate HIF-1a and contribute the ABCG 2 expression and mediated gemcitabine chemoresistance in pancreatic cancer cells. Hypoxic conditions induced HIF-1a binding to target gene sequences in the ABCG 2 promoter, resulting in increased transcription in pancreatic cancer cells. We demonstrated that hypoxia-induced chemoresistance is due to the regulation of ABCG 2 through the activation of ERK1/2/HIF-1a. ABCG 2 could serve as a predictor of gemcitabine response and, potentially, as a chemotherapeutic target in pancreatic cancer. Inhibition of ERK1/2 and HIF-1acould result in increased gemcitabine sensitization in pancreatic cancer with highly expressed ABCG 2 cell member protein.

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Section: Discussionmentioning

confidence: 70%

Hypoxia regulates ABCG₂activity through the activivation of ERK1/2/HIF-1α and contributes to chemoresistance in pancreatic cancer cells

Wang

Wei

et al. 2016

Cancer Biology & Therapy

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“…However, it was not involved in our system, because Mel-18 interacted with HIF-1a and VHL but did not interfere with interaction between HIF-1a and VHL. It has been demonstrated that the Von Hippel-Lindau protein-independent pathway also plays an important role in controlling the HIF-1a protein level (Yee Koh et al, 2008). For example, induction of the sensitive to apoptosis gene, a conserved RING finger protein, or GSK-3b promotes HIF-1a ubiquitination and degradation in a VHL-independent manner (Flugel et al, 2007;Tan et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1α mediated by the PTEN/PI3K/Akt pathway

et al. 2011

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Mel-18 has been implicated in several processes in tumor progression, in which the Akt pathway is involved as an important key molecular event. However, the function of Mel-18 in human cancers has not been fully established yet. Here, we examined the effect of Mel-18 on tumor angiogenesis in human breast cancer, and found that Mel-18 was a novel regulator of HIF-1a. Mel-18 negatively regulated the HIF-1a expression and its target gene VEGF transcription during both normoxia and hypoxia. We demonstrated that Mel-18 regulated the HIF-1a expression and activity via the PI3K/Akt pathway. Loss of Mel-18 downregulated Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression, consequently activating the PI3K/Akt/MDM2 pathway, and leading to an increase of HIF-1a protein level. Mel-18 modulated the HIF-1a transcriptional activity via regulating the cytoplasmic retention of FOXO3a, a downstream effector of Akt, and recruitment of HIF-1a/CBP complex to the VEGF promoter. Furthermore, our data shows that Mel-18 blocked tumor angiogenesis both in vitro and in vivo. Mel-18 overexpression inhibited in vitro tube formation in human umbilical endothelial cells (HUVECs). Xenografts in NOD/SCID mice derived from stably Mel-18 knocked down MCF7 human breast cancer cells showed increased tumor volume, microvessel density, and phospho-Akt and HIF-1a expression levels. In conclusion, our findings provide that Mel-18 is a novel regulator of tumor angiogenesis through regulating HIF-1a and its target VEGF expressions mediated by the PTEN/PI3K/Akt pathway, suggesting a new tumor-suppressive role of Mel-18 in human breast cancer.

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“…[16][17][18] Tumor adaptation to hypoxia is mainly due to the hypoxia-inducible factor (HIF)-1, a key transcription factor that regulates pro-angiogenic factors, angiogenesis and tumor progression in solid tumors. [19][20][21][22][23] HIF-1 is a heterodimeric DNA binding complex highly inducible by hypoxia and is composed of two basic helix-loop-helix proteins, including the constitutive HIF-1b subunit and the hypoxiainducible a-subunit. [19][20][21] Under normoxic conditions HIF-1a has a very short half-life undergoing proteosomal degradation by oxygen-dependent hydroxylation.…”

Section: Introductionmentioning

confidence: 99%

“…[19][20][21][22][23] HIF-1 is a heterodimeric DNA binding complex highly inducible by hypoxia and is composed of two basic helix-loop-helix proteins, including the constitutive HIF-1b subunit and the hypoxiainducible a-subunit. [19][20][21] Under normoxic conditions HIF-1a has a very short half-life undergoing proteosomal degradation by oxygen-dependent hydroxylation. In contrast, under hypoxic condition, hydroxylation is suppressed and HIF-1a protein escapes proteasomal destruction and can accumulate and translocate to the nucleus.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, under hypoxic condition, hydroxylation is suppressed and HIF-1a protein escapes proteasomal destruction and can accumulate and translocate to the nucleus. [19][20][21] HIF-1a is a critical trigger and regulator of tumor associated angiogenesis. 22,23 Interestingly a critical role of HIF-1a in osteoclast formation and regulation has been shown 24,25 as well as its role in the development of osteolytic metastasis in breast cancer model.…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction

et al. 2013

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Hypoxia-inducible transcription factor-1 (HIF-1a) is overexpressed in multiple myeloma (MM) cells within the hypoxic microenvironment. Herein, we explored the effect of persistent HIF-1a inhibition by a lentivirus short hairpin RNA pool on MM cell growth either in vitro or in vivo and on the transcriptional and pro-angiogenic profiles of MM cells. HIF-1a suppression did not have a significant impact on MM cell proliferation and survival in vitro although, increased the antiproliferative effect of lenalidomide. On the other hand, we found that HIF-1a inhibition in MM cells downregulates the pro-angiogenic genes VEGF, IL8, IL10, CCL2, CCL5 and MMP9. Pro-osteoclastogenic cytokines were also inhibited, such as IL-7 and CCL3/MIP-1a. The effect of HIF-1a inhibition was assessed in vivo in nonobese diabetic/severe combined immunodeficiency mice both in a subcutaneous and an intratibial MM model. HIF-1a inhibition caused a dramatic reduction in the weight and volume of the tumor burden in both mouse models. Moreover, a significant reduction of the number of vessels and vascular endothelial growth factors (VEGFs) immunostaining was observed. Finally, in the intratibial experiments, HIF-1a inhibition significantly blocked bone destruction. Overall, our data indicate that HIF-1a suppression in MM cells significantly blocks MM-induced angiogenesis and reduces MM tumor burden and bone destruction in vivo, supporting HIF-1a as a potential therapeutic target in MM.

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HIF-1 regulation: not so easy come, easy go

Cited by 305 publications

References 82 publications

Hypoxia regulates ABCG₂activity through the activivation of ERK1/2/HIF-1α and contributes to chemoresistance in pancreatic cancer cells

Hypoxia regulates ABCG₂activity through the activivation of ERK1/2/HIF-1α and contributes to chemoresistance in pancreatic cancer cells

Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1α mediated by the PTEN/PI3K/Akt pathway

Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction

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HIF-1 regulation: not so easy come, easy go

Cited by 305 publications

References 82 publications

Hypoxia regulates ABCG2activity through the activivation of ERK1/2/HIF-1α and contributes to chemoresistance in pancreatic cancer cells

Hypoxia regulates ABCG2activity through the activivation of ERK1/2/HIF-1α and contributes to chemoresistance in pancreatic cancer cells

Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1α mediated by the PTEN/PI3K/Akt pathway

Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction

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Hypoxia regulates ABCG₂activity through the activivation of ERK1/2/HIF-1α and contributes to chemoresistance in pancreatic cancer cells

Hypoxia regulates ABCG₂activity through the activivation of ERK1/2/HIF-1α and contributes to chemoresistance in pancreatic cancer cells