AMPK inhibitor compound C suppresses cell proliferation by induction of apoptosis and autophagy in human colorectal cancer cells.
OBJECTIVE
AMP-activated protein kinase (AMPK) is a main regulator of energy metabolism through the inhibition of biosynthetic pathways and enhancement of ATP-generating pathways. However, targeting AMPK as anti-tumor therapy remains controversial. In this study, we examined the effect of compound C, a small molecule inhibitor of AMPK, on the proliferation of several human colorectal cancer cell lines with diverse characteristics.


METHODS
Four human colorectal cancer cell lines (HCT116, DLD-1, SW480, and KM12C) were treated with compound C. Cell viability was determined by MTS assay. Cell cycle prolife was analyzed by flow cytometry. Acidic vesicular organelles were detected by acridine orange staining. Protein levels were measured by western blotting.


RESULTS
Compound C inhibited the growth of four cell lines in a dose-dependent manner and caused G(2) /M arrest. Compound C increased sub-G(1) cell population and induced chromatin condensation and cleavage of PARP in HCT116 and KM12C cells, while it induced acidic vesicular formation and conversion of LC3-I to autophagosome-associated LC3-II in DLD-1 and SW480 cells. Survivin, an anti-apoptotic protein, was down-regulated in all cell lines treated with compound C.


CONCLUSIONS
Compound C induces apoptotic or autophagic death in colorectal cancer cells and the preferred death mode is cell type-dependent.
Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, New York, USA. wlyang@nshs.edu
Weng-Lang
WL
Yang
William
W
Perillo
Deanna
D
Liou
Philippe
P
Marambaud
Ping
P
Wang
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D011720:Pyrazoles; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; C516138:dorsomorphin; D055372:AMP-Activated Protein Kinases