RETRACTED ARTICLE: Hypoxia-associated p38 mitogen-activated protein kinase-mediated androgen receptor activation and increased HIF-1α levels contribute to emergence of an aggressive phenotype in prostate cancer

Khandrika, Lakshmipathi; Lieberman, Rachel; Koul, Sweaty; Kumar, Binod; Maroni, Paul; Chandhoke, Ryan; Meacham, Randall B.; Koul, Hari K.

doi:10.1038/onc.2008.476

Cited by 85 publications

(73 citation statements)

References 38 publications

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“…Previous studies have found that hypoxia activated AR only in the presence of androgen (Horii et al, 2007;Park et al, 2012). Others showed unliganded AR transactivation in cells exposed to hypoxia (Khandrika et al, 2009) or hypoxia only activated the AR at low androgen concentrations mimicking the castration-resistant stage (Mitani et al, 2011), involving AR, HIF-1a, and b-catenin forming a ternary complex on AREs (Mitani et al, 2012). Similarly, the effect of AR activation on HIF-mediated transcription was either induction (Mabjeesh et al, 2003;Horii et al, 2007) or no synergistic effect (Park et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Dual Targeting of the Androgen Receptor and Hypoxia-Inducible Factor 1α Pathways Synergistically Inhibits Castration-Resistant Prostate Cancer Cells

et al. 2015

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Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in metastatic castrate-resistant prostate cancer (CRPC). Although enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Given that both AR and hypoxia inducible factor-1 a (HIF-1a) are key regulators of these processes, dual targeting of both signaling axes represents an attractive therapeutic approach. Crosstalk of the AR and HIF-1a signaling pathways were examined in prostate cancer cell lines (LNCaP, 22Rv1) with assays measuring the effect of androgen and hypoxia on AR-dependent and hypoxia-inducible gene transcription, protein expression, cell proliferation, and apoptosis. HIF-1a inhibition was achieved by siRNA silencing HIF-1a or via chetomin, a disruptor of HIF-1a-p300 interactions. In prostate cancer cells, the gene expression of AR targets (KLK3, FKBP5, TMPRSS2) was repressed by HIFsignaling; conversely, specific HIF-1a target expression was induced by dihydrotestosterone-mediated AR signaling. Treatment of CRPC cells with enzalutamide or HIF-1a inhibition attenuated AR-regulated and HIF-1a-mediated gene transcription. The combination of enzalutamide and HIF-1a inhibition was more effective than either treatment alone. Similarly, the combination also reduced vascular endothelial growth factor protein levels. HIF-1a siRNA synergistically enhanced the inhibitory effect of enzalutamide on cell growth in LNCaP and enzalutamide-resistant 22Rv1 cells via increased enzalutamide-induced apoptosis. In conclusion, the combination of enzalutamide with HIF-1a inhibition resulted in synergistic inhibition of AR-dependent and genespecific HIF-dependent expression and prostate cancer cell growth.

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Section: Discussionmentioning

confidence: 99%

Dual Targeting of the Androgen Receptor and Hypoxia-Inducible Factor 1α Pathways Synergistically Inhibits Castration-Resistant Prostate Cancer Cells

et al. 2015

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“…HIF-1a accumulates to a high level in many solid tumors, including breast, prostate, colorectal, and pancreatic cancers (8)(9)(10) but is virtually undetectable in normal, well-oxygenated tissues (11)(12)(13). Cancer cells that contain high levels of HIF-1a are able to survive under extreme conditions, are resistant to therapy, and have a greater potential for metastasis (10,(14)(15)(16)(17)(18). Thus, the linking of HIF-1a levels to 5FU production could in theory attack the most aggressive tumors, while having limited or no effect on well-oxygenated, normal cells.…”

Section: Resultsmentioning

confidence: 99%

“…HIF-1a is a molecular signature of cancer cells that can survive under extreme conditions, are resistant to therapy, and have a greater potential for metastasis (14)(15)(16)(17)(18). A treatment method that could specifically target these cells could significantly improve the effectiveness of cancer treatments when used in combination with traditional therapies.…”

Section: Characterization Of Haps Proteins In Bacteriamentioning

confidence: 99%

A protein therapeutic modality founded on molecular regulation

Wright

Eshleman

et al. 2011

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

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The exquisite specificity of proteins is a key feature driving their application to anticancer therapies. The therapeutic potential of another fundamental property of proteins, their ability to be regulated by molecular cues in their environment, is unknown. Here, we describe a synthetic biology strategy for designing protein therapeutics that autonomously activate a therapeutic function in response to a specific cancer marker of choice. We demonstrate this approach by creating a prodrug-activating enzyme that selectively kills human cancer cells that accumulate the marker hypoxia-inducible factor 1α. This property arises primarily through increased cellular accumulation of the enzyme in the presence of the marker. Our strategy offers a platform for the development of inherently selective protein therapeutics for cancer and other diseases. directed evolution | protein engineering | protein switch | enzyme/prodrug therapy

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“…Notably, VEGF is important in the regulation of normal and abnormal angiogenesis in the ovary (3,4,(13)(14)(15)(16)(17)(18), particularly in the newly formed corpus luteum (19)(20)(21)(22). Hypoxia is a potent stimulus for the expression of VEGF (14,23), as ovulation causes a decline of local oxygen concentration, producing a hypoxic environment, and may be the predominant stimulator for VEGF production in the developing corpus luteum (5,24).…”

Section: Introductionmentioning

confidence: 99%

Expression and contribution of the HIF‑1α/VEGF signaling pathway to luteal development and function in pregnant rats

Zhang

Pan

et al. 2015

Mol Med Report

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Abstract. Vascular endothelial growth factor (VEGF) is vital in normal and abnormal angiogenesis in the ovary, particularly during the early development of the corpus luteum in the ovary. However, the molecular regulation of the expression VEGF during luteal development in vivo remains to be fully elucidated. As the expression of VEGF is mediated by hypoxia-inducible factor (HIF)-1α in luteal cells cultured in vitro, determined in our previous study, the present study was performed to confirm the hypothesis that HIF-1α is induced and then regulates the expression of VEGF and VEGF-dependent luteal development/function in vivo. This was investigated using a pregnant rat model treated with a small-molecule inhibitor of HIF-1α, echinomycin (Ech). The development of the corpus luteum in the pregnant rat ovary was identified via performing assays of the serum progesterone, testosterone and estradiol concentrations by radioimmunoassay, accompanied with determination of the changes in the expression levels of HIF-1α and VEGF by reverse transcription-quantitative polymerase chain reaction at different days of the developmental process. On day 5, serum progesterone levels were markedly increased, whereas serum levels of testosterone and estradiol did not change significantly. On day 17, the highest level of serum progesterone was observed, however, this was not the case for testosterone and estradiol. Further analysis of the expression levels of HIF-1α and VEGF revealed that their changes were consistent with the changes in serum levels of progesterone, which occurred in the development of the corpus luteum in the ovaries of pregnant rats. Further investigation demonstrated that Ech inhibited luteal development through inhibiting the expression of VEGF, mediated by HIF-1α, and subsequent luteal function, which was determined by detecting changes in serum progesterone on days 8 and 14. Taken together, these results demonstrated that HIF-1α-mediated expression of VEGF may be one of the important mechanisms regulating ovarian luteal development in mammals in vivo, which may provide novel strategies in treatment for fertility control and for certain types of ovarian dysfunction, including polycystic ovarian syndrome, ovarian hyperstimulation syndrome and ovarian neoplasia.

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RETRACTED ARTICLE: Hypoxia-associated p38 mitogen-activated protein kinase-mediated androgen receptor activation and increased HIF-1α levels contribute to emergence of an aggressive phenotype in prostate cancer

Cited by 85 publications

References 38 publications

Dual Targeting of the Androgen Receptor and Hypoxia-Inducible Factor 1α Pathways Synergistically Inhibits Castration-Resistant Prostate Cancer Cells

Dual Targeting of the Androgen Receptor and Hypoxia-Inducible Factor 1α Pathways Synergistically Inhibits Castration-Resistant Prostate Cancer Cells

A protein therapeutic modality founded on molecular regulation

Expression and contribution of the HIF‑1α/VEGF signaling pathway to luteal development and function in pregnant rats

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