Methylseleninic acid downregulates hypoxia‐inducible factor‐1α in invasive prostate cancer

Abstract

Alternative strategies are needed to control growth of advanced and hormone refractory prostate cancer. In this regard, we investigated the efficacy of methylseleninic acid (MSeA), a penultimate precursor to the highly reactive selenium metabolite, methylselenol, to inhibit growth of invasive and hormone refractory rat (PAIII) and human (PC-3 and PC-3M) prostate cancer cells. Our results demonstrate that MSeA inhibits PAIII cell growth in vitro as well as reduces weights of tumors generated by PAIII cells treated ex vivo. A significant reduction in the number of metastatic lung foci by MSeA treatment was also noted in Lobund-Wistar rats. The PAIII cells along with PC-3, DU145 and PC-3M cells undergo apoptosis after MSeA treatments in both normoxia and hypoxia. Treatment of metastatic rat and human prostate cancer cell lines with MSeA decreased hypoxiainducible factor-1a (HIF-1a) levels in a dose-dependent manner. Additionally, HIF-1a transcription activity both in normoxic and hypoxic conditions is reduced after MSeA treatment of prostate cancer cells. Furthermore, VEGF and GLUT1, downstream targets of HIF-1a, were also reduced in prostate cancer cells after MSeA treatment. Our study illustrates the efficacy of MSeA in controlling growth of hormone refractory prostate cancer by downregulating HIF-1a, which is possibly occurring through stabilization or increase in prolyl hydroxylase activity.In men with advanced prostate cancer, hormone therapy is accepted as the initial treatment of choice and produces good responses in most patients. However, many patients relapse and become resistant to further hormone manipulation. Radical prostatectomy is recommended for treatment of localized prostate cancer. Unfortunately, local recurrences occur in up to one-third of patients by 5 years after surgery.1 Furthermore, a combination of hormone therapy with radical prostatectomy in patients with localized disease resulted in 5-year disease-free survival of 64%. 2Effective radiation therapy requires the presence of oxygen.3 As a result of rapid mitotic growth and clonal expansion, tumor cells are usually forced away from vessels beyond effective diffusion distance of oxygen and thrive remarkably well within a hypoxic environment. This tumor hypoxia may lead to resistance to radiation and chemotherapy.4 Hypoxia within solid tumors induces hypoxia-inducible factor (HIF)-1a, 5 and its elevation in prostate cancer cells may attribute to enhanced growth rates, survival and increased metastatic potential. 6HIF-1 is a heterodimer composed of an inducible a-subunit that confers the sensitivity to oxygen and a constitutively expressed b-subunit, aryl hydrocarbon receptor nuclear translocator.7 Under normoxic conditions after a post-translational hydroxylation by prolyl hydroxylase (PHD), HIF-1a interacts with tumor suppressor von-Hippel-Lindau protein and is rapidly degraded via ubiquitin-dependent proteasome pathway. 8 Hypoxia induces a rapid increase in HIF-1a protein stability and transcriptional activity, 9 resulting in the activat...

Prolyl hydroxylase 2 dependent and Von-Hippel-Lindau independent degradation of Hypoxia-inducible factor 1 and 2 alpha by selenium in clear cell renal cell carcinoma leads to tumor growth inhibition

“…Consistent with our data, published results show the degradation of constitutively expressed HIF-1α in prostate cancer [38] and hypoxia induced HIF-1α in B-cell lymphoma [39] by selenium. These findings show that both hypoxia induced and constitutively expressed HIF-α are inhibited by selenium suggesting that selenium could inhibit growth of tumors expressing HIF-1α, HIF-2α or both.…”

“…Our recent report [22] and study by Sinha et al, [38] demonstrated stabilization of PHDs by MSA leads to the degradation of HIF-1α. HIF-1α degradation through VHL dependent and independent pathways is known.…”

HIF-1α silencing suppresses growth of lung adenocarcinoma A549 cells through induction of apoptosis

“…Overexpression of HIF-1α has been detected in >70% of solid tumors. While upregulation or activation of HIF-1α promotes tumor growth, downregulation or loss of HIF-1α activity has been demonstrated to markedly decrease tumor growth, vascularization and energy metabolism (8)(9)(10)(11). The suppression of HIF-1α expression by RNA interference (RNAi) has been shown to be an effective method of cancer therapy (12).…”

Is Selenium a Potential Treatment for Cancer Metastasis?

“…Two weeks after PAIII cells were injected through the tail vein, rats received daily MSA supplementation for two weeks. This treatment significantly reduced the metastatic lung foci found in the MSA-fed rats [68]. This particular experiment did not address the effect of MSA on primary tumors or the events that happen before cancer cells arrive in the secondary organs.…”