Inhibition of macroautophagy by bafilomycin A1 lowers proliferation and induces apoptosis in colon cancer cells.
Macroautophagy is a process by which cytoplasmic content and organelles are sequestered by double-membrane bound vesicles and subsequently delivered to lysosomes for degradation. Macroautophagy serves as a major intracellular pathway for protein degradation and as a pro-survival mechanism in time of stress by generating nutrients. In the present study, bafilomycin A(1), a vacuolar type H(+)-ATPase inhibitor, suppresses macroautophagy by preventing acidification of lysosomes in colon cancer cells. Diminished macroautophagy was evidenced by the accumulation of undegraded LC3 protein. Suppression of macroautophagy by bafilomycin A(1) induced G(0)/G(1) cell cycle arrest and apoptosis which were accompanied by the down-regulation of cyclin D(1) and cyclin E, the up-regulation of p21(Cip1) as well as cleavages of caspases-3, -7, -8, and -9 and PARP. Further investigation revealed that bafilomycin A(1) increased the phosphorylation of ERK, JNK, and p38. In this regard, p38 inhibitor partially reversed the anti-proliferative effect of bafilomycin A(1). To conclude, inhibition of macroautophagy by bafilomycin A(1) lowers G(1)-S transition and induces apoptosis in colon cancer cells. Our results not only indicate that inhibitors of macroautophagy may be used therapeutically to inhibit cancer growth, but also delineate the relationship between macroautophagy and apoptosis.
Wu
Ya Chun
YC
Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, PR China.
Wu
William Ka Kei
WK
Li
Youming
Y
Yu
Le
L
Li
Zhi Jie
ZJ
Wong
Clover Ching Man
CC
Li
Hai Tao
HT
Sung
Joseph Jao Yiu
JJ
Cho
Chi Hin
CH
D017209:Apoptosis; D001343:Autophagy / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000473:pathology*; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D022162:Cytoplasmic Vesicles / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; C477012:MAP1LC3A protein, human; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D019938:Cyclin D1; C040929:bafilomycin A1; D011065:Poly(ADP-ribose) Polymerases; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases