Negation of the cancer-preventive actions of selenium by over-expression of protein kinase C  and selenoprotein thioredoxin reductase

Abstract

Selenium prevents cancer in some cases but fails to do so in others. Selenium's failure in this respect may be due to the development of resistance to its chemopreventive actions. Selenocompounds induce a variety of cancer-preventive actions in tumor cells, but these actions may be limited by the low concentrations of free selenocompounds able to reach cells from the plasma. Therefore, we have sought to identify the chemopreventive action requiring the lowest concentration of the redox-active form of selenium, methylseleninic acid (MSA). At submicromolar concentrations, MSA inhibited the malignant transformation of RWPE-1 prostate epithelial cells. In contrast, in already transformed prostate cancer cells, selenium in the micromolar range was required to inhibit cell growth and invasion and to induce apoptosis. The role of protein kinase C (PKC) in these cellular processes, especially the moderately selenium-sensitive PKCepsilon, was demonstrated using PKC-specific inhibitors and small interfering RNA. PKCepsilon levels inversely correlated with cellular sensitivity to MSA. An over-expression of PKCepsilon minimized MSA-induced inhibition of RWPE-1 cell transformation and induction of apoptosis. Thioredoxin reductase (TR), a selenoprotein, reversed the MSA-induced inactivation of PKC isoenzymes. High TR expression in advanced prostate cancer cells correlated with resistance to MSA. Furthermore, inhibition of TR by its specific inhibitor, auranofin, resulted in increased sensitivity of prostate cancer cells to MSA. Collectively, these results suggest that the cancer-preventive actions of selenium may be negated both by an over-expression of PKCepsilon, which is a redox-sensitive target for MSA, and by the selenoprotein TR, which reverses PKC sulfhydryl redox modification.

Protein Kinase C Epsilon and Genetic Networks in Osteosarcoma Metastasis

“…Literature searches of the genes contained in the highly significant network results showed that PRKCε has been characterized in progression of prostate [82,83,84,85,86,87], breast [88,89], and renal cancers [90], as well as tumorigenesis of squamous cell carcinoma (non-melanoma skin [91,92,93,94,95], and head and neck [96,97,98,99]), as well as non-small cell lung cancer [100,101,102,103]. Additionally high expression of GNB2 is associated with an aggressive form of pulmonary adenocarcinoma (mixed adenocarcinoma with bronchioalveolar features), and shorter overall survival for patients with these tumors [104].…”

“…The effect of high PRKCε expression may be related to the proliferation effects of the IGF-1 pathway, as this study provides evidence for the IGF-1 dependent induction of PRKCε protein expression. PRKCε may support other cellular processes entirely, as it is known to promote pro-metastatic phenotypes of many other cancers [82,83,84,85,86,87,91,92,93,94,95,96,97,98,99,100,101,102,103]. …”

Cancer chemoprevention research with selenium in the post-SELECT era: Promises and challenges

“…The same group subsequently showed that MSeA at submicromolar concentrations prevented the transformation of prostate epithelial cells but micromolar levels were required to inhibit cell growth, invasion and induce apoptosis in PCa cells (82). Over-expression of PKCepsilon attenuated MSeA inhibition of epithelial cell transformation and PCa cell apoptosis.…”

“…Over-expression of PKCepsilon attenuated MSeA inhibition of epithelial cell transformation and PCa cell apoptosis. In addition, increased TrxR expression caused resistance to MSeA treatment and inhibition of TrxR increased the sensitivity of cancer cells to MSeA (82). These studies suggest that both PKCepsilon and TrxR can negate the anti-cancer efficacy of MSeA.…”

Alteration of Thioredoxin Reductase 1 Levels in Elucidating Cancer Etiology

“…For example, TR1 is over-expressed in many cancers and cancer cell lines (Arnér, 2009; Arnér and Holmgren 2006; Biaglow and Miller, 2005; Fujino et al ., 2006; Gundimeda et al , 2009; Hedström et al , 2009; Rundlöf et al , 2004; Yoo et al , 2007a), and this selenoenzyme may have similar roles in malignant and normal cells in preventing or reducing oxidative stress. Numerous inhibitors of TR1 and other potent anti-cancer drugs that target TR1 activity and alter cancer-related properties also suggest that this protein has a major role in promoting and/or sustaining cancer (see Arnér, 2009; Chew et al , 2009, Gandin et al , 2009; Honeggar et al , 2009; Lam et al , 2009; Li et al , 2009; Selenius et al , 2009; Urig and Becker, 2006; Yan et al , 2009; Yoo et al , 2007a and references therein).…”