Silencing of HIF-1α suppresses tumorigenicity of renal cell carcinoma through induction of apoptosis

Xu, Kang; Ding, Qianqian; Zheng, Fang; Zheng, Jiaojiao; Gao, Peiye; Lu, Yuan; Zhang, Y

doi:10.1038/cgt.2009.66

Cited by 27 publications

(19 citation statements)

References 34 publications

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“…Furthermore, we demonstrate that this effect is mediated by HIF-1α. This is consistent with previous reports that knockdown of HIF-1α reduces migration potential and formation of tumor spheres in glioma cells (21), expansion of CD133 + CSCs in glioblastoma (9), and tumorigenicity of renal cell carcinoma (22).…”

Section: Discussionsupporting

confidence: 93%

Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia

Conley

Gheordunescu

Kakarala

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

582

499

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Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstrate that by generating intratumoral hypoxia in human breast cancer xenografts, the antiangiogenic agents sunitinib and bevacizumab increase the population of cancer stem cells. In vitro studies revealed that hypoxia-driven stem/progenitor cell enrichment is primarily mediated by hypoxia-inducible factor 1α. We further show that the Akt/β-catenin cancer stem cell regulatory pathway is activated in breast cancer cells under hypoxic conditions in vitro and in sunitinib-treated mouse xenografts. These studies demonstrate that hypoxia-driven cancer stem cell stimulation limits the effectiveness of antiangiogenic agents, and suggest that to improve patient outcome, these agents might have to be combined with cancer stem cell-targeting drugs.antiangiogenesis | HIF-1α

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Section: Discussionsupporting

confidence: 93%

Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia

Conley

Gheordunescu

Kakarala

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

582

499

View full text Add to dashboard Cite

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“…HIF-1a mRNA was reduced by 90% at 72 hours after transfection, whereas the protein was reduced by 70% 5 days after transfection, which implied its strong stabilization. HIF-1a knockdown affected MMECs adhesion, spreading, and migration, as others have found in cells of malignant glioma (35) and renal carcinoma (36). It also inhibited MMEC angiogenesis in vitro (Matrigel) and in vivo (CAM) assays.…”

Section: Discussionsupporting

confidence: 69%

HIF-1α of Bone Marrow Endothelial Cells Implies Relapse and Drug Resistance in Patients with Multiple Myeloma and May Act as a Therapeutic Target

Ria

Catacchio

Berardi

et al. 2014

Clinical Cancer Research

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Purpose: To investigate the role of hypoxia-inducible factor-1a (HIF-1a) in angiogenesis and drug resistance of bone marrow endothelial cells of patients with multiple myeloma.Experimental Design: HIF-1a mRNA and protein were evaluated in patients with multiple myeloma endothelial cells (MMEC) at diagnosis, at relapse after bortezomib-or lenalidomide-based therapies or on refractory phase to these drugs, at remission; in endothelial cells of patients with monoclonal gammapathies of undetermined significance (MGUS; MGECs), and of those with benign anemia (controls). The effects of HIF-1a inhibition by siRNA or panobinostat (an indirect HIF-1a inhibitor) on the expression of HIF-1a proangiogenic targets, on MMEC angiogenic activities in vitro and in vivo, and on overcoming MMEC resistance to bortezomib and lenalidomide were studied. The overall survival of the patients was also observed.Results: Compared with the other endothelial cell types, only MMECs from 45% of relapsed/refractory patients showed a normoxic HIF-1a protein stabilization and activation that were induced by reactive oxygen species (ROS). The HIF-1a protein correlated with the expression of its proangiogenic targets. The HIF-1a inhibition by either siRNA or panobinostat impaired the MMECs angiogenesis-related functions both in vitro and in vivo and restored MMEC sensitivity to bortezomib and lenalidomide. Patients with MMECs expressing the HIF-1a protein had shorter overall survival.Conclusions: The HIF-1a protein in MMECs may induce angiogenesis and resistance to bortezomib and lenalidomide and may be a plausible target for the antiangiogenic management of patients with well-defined relapsed/refractory multiple myeloma. It may also have prognostic significance. Clin Cancer Res; 20(4); 847-58. Ó2013 AACR.

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“…Conversely, some studies suggest a tumor suppressor role for HIFα (Shen et al 2011). The expression of HIF-1α is related to a favorable prognosis in human neuroblastoma and renal cell carcinomas (Xu et al 2010;Keith et al 2012; Medina Villaamil et al 2012). HIF-2α also induces apoptosis in glioma and inhibits oncogenic signaling and activates a tumor suppressor gene in NSCLC (Acker et al 2005;Mazumdar et al 2010).…”

Section: Discussionmentioning

confidence: 99%

WSB1 promotes tumor metastasis by inducing pVHL degradation

et al. 2015

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The von Hippel-Lindau tumor suppressor pVHL is an E3 ligase that targets hypoxia-inducible factors (HIFs). Mutation of VHL results in HIF up-regulation and contributes to processes related to tumor progression such as invasion, metastasis, and angiogenesis. However, very little is known with regard to post-transcriptional regulation of pVHL. Here we show that WD repeat and SOCS box-containing protein 1 (WSB1) is a negative regulator of pVHL through WSB1's E3 ligase activity. Mechanistically, WSB1 promotes pVHL ubiquitination and proteasomal degradation, thereby stabilizing HIF under both normoxic and hypoxic conditions. As a consequence, WSB1 up-regulates the expression of HIF-1α's target genes and promotes cancer invasion and metastasis through its effect on pVHL. Consistent with this, WSB1 protein level negatively correlates with pVHL level and metastasis-free survival in clinical samples. This work reveals a new mechanism of pVHL's regulation by which cancer acquires invasiveness and metastatic tendency.

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Silencing of HIF-1α suppresses tumorigenicity of renal cell carcinoma through induction of apoptosis

Cited by 27 publications

References 34 publications

Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia

Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia

HIF-1α of Bone Marrow Endothelial Cells Implies Relapse and Drug Resistance in Patients with Multiple Myeloma and May Act as a Therapeutic Target

WSB1 promotes tumor metastasis by inducing pVHL degradation

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