LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1α via upregulation of VHL in a colon cancer cell line

Lee, Kyeong; Kang, Jung Eun; Park, Song‐Kyu; Jin, Yinglan; Chung, Kyung‐Sook; Kim, Hwan‐Mook; Lee, Kiho; Kang, Moo Rim; Lee, Myung Kyu; Song, Kyung Bin; Yang, Eungyeong; Lee, Jung-Jun; Won, Misun

doi:10.1016/j.bcp.2010.06.018

Cited by 126 publications

(101 citation statements)

References 39 publications

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“…Strikingly, gramicidin A reduced HIF expression even in hypoxic conditions. Although hypoxia (1% O 2 ) limits PHD-mediated hydroxylation by depleting molecular oxygen, it does not completely abolish it (34). We determined that gramicidin A increases the expression of VHL protein to accelerate O 2 -dependent degradation of HIF.…”

Section: Discussionmentioning

confidence: 93%

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Gramicidin A Blocks Tumor Growth and Angiogenesis through Inhibition of Hypoxia-Inducible Factor in Renal Cell Carcinoma

David

Owens

Inge

et al. 2014

Molecular Cancer Therapeutics

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Ionophores are hydrophobic organic molecules that disrupt cellular transmembrane potential by permeabilizing membranes to specific ions. Gramicidin A is a channel-forming ionophore that forms a hydrophilic membrane pore that permits the rapid passage of monovalent cations. Previously, we found that gramicidin A induces cellular energy stress and cell death in renal cell carcinoma (RCC) cell lines. RCC is a therapy-resistant cancer that is characterized by constitutive activation of the transcription factor hypoxia-inducible factor (HIF). Here, we demonstrate that gramicidin A inhibits HIF in RCC cells. We found that gramicidin A destabilized HIF-1a and HIF-2a proteins in both normoxic and hypoxic conditions, which in turn diminished HIF transcriptional activity and the expression of various hypoxia-response genes. Mechanistic examination revealed that gramicidin A accelerates O 2 -dependent downregulation of HIF by upregulating the expression of the von Hippel-Lindau (VHL) tumor suppressor protein, which targets hydroxylated HIF for proteasomal degradation. Furthermore, gramicidin A reduced the growth of human RCC xenograft tumors without causing significant toxicity in mice. Gramicidin A-treated tumors also displayed physiologic and molecular features consistent with the inhibition of HIF-dependent angiogenesis. Taken together, these results demonstrate a new role for gramicidin A as a potent inhibitor of HIF that reduces tumor growth and angiogenesis in VHLexpressing RCC. Mol Cancer Ther; 13(4); 788-99. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 93%

“…These data demonstrate that VHL is essential for gramicidin A-mediated destabilization of HIF. Although hypoxia reduces proline hydroxylation of HIF, it does not completely abolish it (34). Because gramicidin A treatment reduced HIF expression even in hypoxic conditions ( Fig.…”

Section: Gramicidin a Upregulates Vhl Protein Expressionmentioning

confidence: 91%

Gramicidin A Blocks Tumor Growth and Angiogenesis through Inhibition of Hypoxia-Inducible Factor in Renal Cell Carcinoma

David

Owens

Inge

et al. 2014

Molecular Cancer Therapeutics

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“…In this study, we showed that UA was able to inhibit hypoxia-induced expression of HIF-1α and its downstream effector MDR1, through which it sensitized colon cancer cells to chemotherapeutic drugs under hypoxic conditions. CRC cells are exposed to the hypoxic environment pathologically, and HIF-1α accumulates in those cells partly due to impaired degradation (Lee et al, 2010). In addition, treatment of chemotherapeutic drugs can also stimulate HIF-1α transcription even in cells under normoxic conditions (Cao et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α

Shan

Xuan

Zhang

et al. 2016

J. Zhejiang Univ. Sci. B

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Abstract:Objective: To explore the efficacy of ursolic acid in sensitizing colon cancer cells to chemotherapy under hypoxia and its underlying mechanisms. Methods: Three colon cancer cell lines (RKO, LoVo, and SW480) were used as in vitro models. 5-Fluorouracil (5-FU) and oxaliplatin were used as chemotherapeutic drugs. Cell viability and apoptosis were tested to evaluate the sensitivity of colon cancer cells to chemotherapy. The transcription and expression levels of hypoxia-inducible factor-1α (HIF-1α), multidrug resistance gene 1 (MDR1), and vascular endothelial growth factors (VEGF) were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting. Cycloheximide and MG132 were used to inhibit protein synthesis and degradation, respectively. In vitro tube formation assay was used to evaluate angiogenesis. Results: We demonstrated the chemosensitizing effects of ursolic acid with 5-FU and oxaliplatin in three colon cancer cell lines under hypoxia. This effect was correlated to its inhibition of MDR1 through HIF-1α. Moreover, ursolic acid was capable of inhibiting HIF-1α accumulation with little effects on its constitutional expression in normoxia. In addition, ursolic acid also down-regulated VEGF and inhibited tumor angiogenesis. Conclusions: Ursolic acid exerted chemosensitizing effects in colon cancer cells under hypoxia by inhibiting HIF-1α accumulation and the subsequent expression of the MDR1 and VEGF.

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“…In addition, other promising therapeutic strategies for eradicating the highly aggressive and chemoresistant PC cells may consist of targeting the deregulated metabolic pathways and specific signaling elements such as PI3K/Akt/mTOR, NF-κB, HIF-1α and 2α and MIC-1. These elements are induced under normoxic or hypoxic conditions and may provide critical functions for PC cell survival, invasion and metastasis; angiogenesis; and/or treatment resistance ( Figure 3) (29,46,47,129,133,140,(146)(147)(148)(211)(212)(213)(214)(215)(216)(217)(218). Consistent with this finding, the inhibition of glycolysis by using 2-deoxy-Dglucose (2-DG), alone or in combination with other anticancer agents such as pioglitazone, a microtubule disruptor, 2-methoxyoestradiol-3,17-O,O-bissulphamate (STX140) or metformin, which acts at least in part by inhibiting 2-DG-induced autophagy, has been shown to induce cytotoxic effects on the highly proliferative PC cells, including multicellular tumor spheroids from metastatic PC cells, and inhibit tumor growth in vivo (Figure 3) (147,148,212,213).…”

Section: Other Anticancer Agents Targeting Pc-and Metastasis-initiatimentioning

confidence: 99%

“…It has also been noted that the inhibition of glycolysis by either 2-DG or iodoacetate downregulated P-glycoprotein expression and inhibited the efflux of doxorubicin in multicellular tumor spheroids generated from metastatic and AI DU145 PC cells, suggesting that this therapeutic strategy may be effective for reversing the multidrug resistance phenotype of PC cells (146). In this regard, the downregulation of COX-2, HIF-1α and/or HIF-2α expression levels or activities also constitute other potential strategies to inhibit glycolysis, tumor angiogenesis and eradicate invasive and metastatic PC cells (Figure 3) (29,46,47,133,140,(214)(215)(216). Consistently, it has been reported that the targeting of HIF-1α and/or HIF-2α in PC cells by RNA silencing or using a specific inhibitor of HIF-1α, PX-478 (S-2-amino-3-[4′-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride), or inhibitor of the proteasomal degradation of HIF-1α and/or HIF-2α such as ascorbic acid or zinc inhibited their invasive ability in vitro and tumor formation and lung metastases in vivo (Figure 3) (47,206,219).…”

Section: Other Anticancer Agents Targeting Pc-and Metastasis-initiatimentioning

confidence: 99%

Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

Mimeault

Batra

2011

Mol Med

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Recent gene expression profiling analyses and gain-and loss-of-function studies performed with distinct prostate cancer (PC) cell models indicated that the alterations in specific gene products and molecular pathways often occur in PC stem/progenitor cells and their progenies during prostate carcinogenesis and metastases at distant sites, including bones. Particularly, the sustained activation of epidermal growth factor receptor (EGFR), hedgehog, Wnt/β-catenin, Notch, hyaluronan (HA)/CD44 and stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) during the epithelial-mesenchymal transition (EMT) process may provide critical functions for PC progression to locally invasive, metastatic and androgen-independent disease states and treatment resistance. Moreover, an enhanced glycolytic metabolism in PC stem/progenitor cells and their progenies concomitant with the changes in their local microenvironment, including the induction of tumor hypoxia and release of diverse soluble factors by tumor myofibroblasts, also may promote the tumor growth, angiogenesis and metastases. More particularly, these molecular transforming events may cooperate to upregulate Akt, nuclear factor (NF)-κB, hypoxia-inducible factors (HIFs) and stemness gene products such as Oct3/4, Sox2, Nanog and Bmi-1 in PC cells that contribute to their acquisition of high self-renewal, tumorigenic and invasive capacities and survival advantages during PC progression. Consequently, the molecular targeting of these deregulated gene products in the PC-and metastasis-initiating cells and their progenies represent new promising therapeutic strategies of great clinical interest for eradicating the total PC cell mass and improving current antihormonal treatments and docetaxel-based chemotherapies, thereby preventing disease relapse and the death of PC patients.

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LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1α via upregulation of VHL in a colon cancer cell line

Cited by 126 publications

References 39 publications

Gramicidin A Blocks Tumor Growth and Angiogenesis through Inhibition of Hypoxia-Inducible Factor in Renal Cell Carcinoma

Gramicidin A Blocks Tumor Growth and Angiogenesis through Inhibition of Hypoxia-Inducible Factor in Renal Cell Carcinoma

Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α

Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

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