Remarkable inhibition of mTOR signaling by the combination of rapamycin and 1,4-phenylenebis(methylene)selenocyanate in human prostate cancer cells.
Preclinical studies and clinical analyses have implicated the mammalian target of rapamycin (mTOR) pathway in the progression of prostate cancer, suggesting mTOR as a potential target for new therapies. mTOR, a serine/threonine kinase, belongs to two distinct signaling complexes: mTORC1 and mTORC2. We previously showed that the synthetic organoselenium compound, p-XSC, effectively inhibits viability and critical signaling molecules (e.g., androgen receptor, Akt) in androgen responsive (AR) and androgen independent (AI) human prostate cancer cells. On the basis of its inhibition of Akt, we hypothesized that p-XSC modulates mTORC2, an upstream regulator of the kinase. We further hypothesized that combining p-XSC with rapamycin, an mTORC1 inhibitor, would be an effective combinatory strategy for the inhibition of prostate cancer. The effects of p-XSC and rapamycin, alone or in combination, on viability and mTOR signaling were examined in AR LNCaP prostate cancer cells and AI C4-2 and DU145 cells. Phosphorylation of downstream targets of mTORC1 and mTORC2 was analyzed by immunoblotting. The interaction of mTORC1- and mTORC2-specific proteins with mTOR was probed through immunoprecipitation and immunoblotting. p-XSC inhibited phosphorylation of mTORC2 downstream targets, Akt and PCKα, and decreased the levels of rictor, an mTORC2-specific protein, coimmunoprecipitated with mTOR in C4-2 cells. The combination of p-XSC and rapamycin more effectively inhibited viability and mTOR signaling in C4-2, LNCaP and DU145 cells than either agent individually.
Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Penn State Hershey Cancer Institute, Hershey, PA PA 17033, USA.
Nicole D
ND
Facompre
Indu
I
Sinha
Karam
K
El-Bayoumy
John T
JT
Pinto
Raghu
R
Sinha
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002352:Carrier Proteins / Q000032:analysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D002352:Carrier Proteins; D016566:Organoselenium Compounds; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C074153:1,4-phenylenebis(methylene)selenocyanate; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus