title: 1,4-phenylenebis(methylene)selenocyanate, but not selenomethionine, inhibits androgen receptor and Akt signaling in human prostate cancer cells.
abstract: The lack of treatment for worried-well patients with high-grade prostatic intraepithelial neoplasia combined with issues of recurrence and hormone resistance in prostate cancer survivors remains a major public health obstacle. The long latency of prostate cancer development provides an opportunity to intervene with agents of known mechanisms at various stages of disease progression. A number of signaling cascades have been shown to play important roles in prostate cancer development and progression, including the androgen receptor (AR) and phosphatidylinositol 3-kinase/Akt signaling pathways. Crosstalk between these two pathways is also thought to contribute to progression and hormone-refractory prostate disease. Our initial investigations show that the naturally occurring organoselenium compound selenomethionine (SM) and the synthetic 1,4-phenylenebis(methylene)selenocyanate (p-XSC) can inhibit human prostate cancer cell viability; however, in contrast to SM, p-XSC is active at physiologically relevant doses. In the current investigation, we show that p-XSC, but not an equivalent dose of SM, alters molecular targets and induces apoptosis in androgen-responsive LNCaP and androgen-independent LNCaP C4-2 human prostate cancer cells. p-XSC effectively inhibits AR expression and transcriptional activity in both cell lines. p-XSC also decreases Akt phosphorylation as well as Akt-specific phosphorylation of the AR. Inhibition of Akt, however, does not fully attenuate p-XSC-mediated downregulation of AR activity, suggesting that inhibition of AR signaling by p-XSC does not occur solely through alterations in the phosphatidylinositol 3-kinase/Akt survival pathway. Our data suggest that p-XSC inhibits multiple signaling pathways in prostate cancer, likely accounting for the downstream effects on proliferation and apoptosis.
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Penn State Hershey Cancer Institute, Hershey, 17033, USA.
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Facompre
authors.forename: Karam
authors.initials: K
authors.lastname: El-Bayoumy
authors.forename: Yuan-Wan
authors.initials: YW
authors.lastname: Sun
authors.forename: John T
authors.initials: JT
authors.lastname: Pinto
authors.forename: Raghu
authors.initials: R
authors.lastname: Sinha
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D008954:Models, Biological; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology*; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism*; D012645:Selenomethionine / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D016566:Organoselenium Compounds; D011944:Receptors, Androgen; C074153:1,4-phenylenebis(methylene)selenocyanate; D012645:Selenomethionine; D051058:Oncogene Protein v-akt