Combined inhibition of MEK and mTOR signaling inhibits initiation and progression of colorectal cancer.
The role of the mTOR signal pathway in colorectal cancer (CRC) pathogenesis remains unclear, and the combination effect of PD98059 (an inhibitor for MEK) and rapamycin (an inhibitor for mTOR) on CRC is still unknown. Here, we found that combination treatment with PD98059 and rapamycin suppressed the proliferation of CRC cells, induced apoptosis, arrested cell cycle, and reduced the incidence and volume of CRC in mice, as well as inhibited phosphorylation of mTOR and the MEK signal pathway components, of which the effects were more significant than single-drug treatments. These findings indicate that PD98059 combined with rapamycin appears to be a promising strategy for inhibiting the initiation, and progression of CRC, which may provide a novel strategy for CRC prevention.
Zhang
Yan-Jie
YJ
Shanghai Institute of Digestive Disease, Shanghai Jiaotong University School of Medicine Renji Hospital, Shanghai, China.
Tian
Xiao-Qing
XQ
Sun
Dan-Feng
DF
Zhao
Shu-Liang
SL
Xiong
Hua
H
Fang
Jing-Yuan
JY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases
D005419:Flavonoids; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D020123:Sirolimus