The rapamycin analog CCI-779 is a potent inhibitor of pancreatic cancer cell proliferation.
We present immunohistochemical evidence that the mTOR/p70s6k pathway is activated in pancreatic tumors and show that the mTOR inhibitor and rapamycin analog CCI-779 potently suppresses the proliferation of pancreatic cancer cells. Consistent with a recent study, CCI-779 increased c-Jun phosphorylation (Ser63) in a dose- and time-dependent manner, and induced apoptosis in p53-defective BxPC-3 cells. In contrast to the study, however, we observed that CCI-779 concomitantly increased c-Jun protein levels and that its ability to induce apoptosis might not require the activated c-Jun. Furthermore, CCI-779 neither induced c-Jun phosphorylation in other p53-defective pancreatic cancer cells (MiaPaCa-2) nor inhibited their proliferation. c-Jun, in fact, appeared to be partly responsible for the resistance of MiaPaCa-2 cells to CCI-779. Together, these results indicate a complex role for c-Jun in cellular responses to CCI-779 and provide an important basis for investigating CCI-779 further as a potential therapeutic agent for pancreatic tumors.
Asano
Takayuki
T
Department of Gastrointestinal Medical Oncology, Unit 426, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Yao
Yixin
Y
Zhu
Jijiang
J
Li
Donghui
D
Abbruzzese
James L
JL
Reddy
Shrikanth A
SA
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016755:Proto-Oncogene Proteins c-jun; C401859:temsirolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus