Targeting Cdc37 inhibits multiple signaling pathways and induces growth arrest in prostate cancer cells.
Members of the 90-kDa heat shock protein (HSP90) family are known to bind and stabilize intermediates in a wide variety of cell signaling pathways and contribute to their dysregulation in cancer. An important intracellular cofactor for HSP90 is Cdc37, a protein with a broad role in fostering the activities of protein kinases. By targeting Cdc37 using RNA interference, we have shown that the loss of Cdc37 function induces irreversible growth arrest in androgen receptor-positive and -negative prostate carcinoma cells. In contrast to HSP90-directed agents, Cdc37 targeting seems to affect cancer cells through a distinct mechanism and does not significantly deplete the intracellular levels of most known HSP90 client proteins. Instead, Cdc37 depletion inhibits cellular kinase activity and flux through growth-promoting signal transduction cascades. We show that the loss of Cdc37 leads to reduced activity of the Erk, Akt, mTOR, and androgen-induced pathways. We have also discovered synergistic interactions between Cdc37 inactivation and the HSP90-inhibitory anticancer drug 17-(allylamino)-17-demethoxygeldanamycin (17AAG). These interactions involve enhanced degradation of proteins essential for growth and inhibition of 17AAG-induced expression of the antiapoptotic HSP70. Thus, Cdc37 is essential for maintaining prostate tumor cell growth and may represent a novel target in the search for multitargeted therapies based on the HSP90 chaperone system.
Gray
Phillip J
PJ
Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Stevenson
Mary Ann
MA
Calderwood
Stuart K
SK
D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D018833:Chaperonins / Q000037:antagonists & inhibitors / Q000235:genetics*; D003114:Colony-Forming Units Assay; D017930:Genes, Reporter; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010957:Plasmids; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D016337:RNA, Catalytic / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D016337:RNA, Catalytic; D012334:RNA, Neoplasm; C418481:hairpin ribozyme; D018833:Chaperonins