Ras inhibition results in growth arrest and death of androgen-dependent and androgen-independent prostate cancer cells.
Prostate cancer is one of the most frequently diagnosed cancers in human males. Progression of these tumors is facilitated by autocrine/paracrine growth factors which activate critical signaling cascades that promote prostate cancer cell growth, survival and migration. Among these, Ras pathways have a major role. Here we examined the effect of the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS), on growth and viability of androgen-dependent and androgen-independent prostate cancer cells. FTS downregulated Ras, inhibited signaling to Akt and reduced the levels of cell-cycle regulatory proteins including cyclin D1, p-RB, E2F-1 and cdc42 in LNCaP and PC3 cells. Consequently the anchorage-dependent and anchorage-independent growth of LNCaP and PC3 cells were inhibited. FTS also induced apoptotic cell death which was inhibited by the broad-spectrum caspases inhibitor, Boc-asp-FMK. Our study demonstrated that androgen-dependent and androgen-independent prostate cancer cells require active Ras for growth and survival. Ras inhibition by FTS results in growth arrest and cell death. FTS may be qualified as a potential agent for the treatment of prostate cancer.
Erlich
Shlomit
S
Department of Neurobiochemistry, Tel-Aviv University, Ramat-Aviv 69978, Israel.
Tal-Or
Pazit
P
Liebling
Ronit
R
Blum
Roy
R
Karunagaran
Devarajan
D
Kloog
Yoel
Y
Pinkas-Kramarski
Ronit
R
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000728:Androgens / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008297:Male; D065636:Myotonin-Protein Kinase; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology
D000590:Amino Acid Chloromethyl Ketones; D000728:Androgens; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D050687:E2F1 Transcription Factor; D012459:Salicylates; D015842:Serine Proteinase Inhibitors; C417985:butyloxycarbonyl-aspartyl-fluoromethyl ketone; C093323:farnesylthiosalicylic acid; D019938:Cyclin D1; D005204:Farnesol; C118666:CDC42BPB protein, human; D011505:Protein-Tyrosine Kinases; D065636:Myotonin-Protein Kinase; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins