Negation of the cancer-preventive actions of selenium by over-expression of protein kinase Cepsilon and selenoprotein thioredoxin reductase.
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.
Gundimeda
Usha
U
Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089-9112, USA.
Schiffman
Jason Eric
JE
Gottlieb
Simcha Neeli
SN
Roth
Brandon Ian
BI
Gopalakrishna
Rayudu
R
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008770:Methylnitrosourea / Q000633:toxicity; D009361:Neoplasm Invasiveness; D016566:Organoselenium Compounds / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000517:prevention & control; D051744:Protein Kinase C-epsilon / Q000502:physiology*; D013880:Thioredoxin-Disulfide Reductase / Q000502:physiology*
D016588:Anticarcinogenic Agents; D007211:Indoles; D008301:Maleimides; D016566:Organoselenium Compounds; D008770:Methylnitrosourea; C008493:methylselenic acid; D013880:Thioredoxin-Disulfide Reductase; C497255:PRKCE protein, human; D051744:Protein Kinase C-epsilon; C088060:bisindolylmaleimide