Inhibition of macroautophagy by bafilomycin A{sub 1} 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...

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Published in:Biochemical and biophysical research communications 2009-05, Vol.382 (2)
Main Authors: Wu, Ya Chun, Department of Pharmacology, Basic Medical Sciences Building, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, Wu, William Ka Kei, Institute of Digestive Diseases, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, Li, Youming, Yu, Le, Li, Zhi Jie, Wong, Clover Ching Man, Li, Hai Tao, Sung, Joseph Jao Yiu, Cho, Chi Hin
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
ACIDIFICATION
APOPTOSIS
CELL CONSTITUENTS
CELL CYCLE
CLEAVAGE
GENE REGULATION
INHIBITION
LARGE INTESTINE
LYSOSOMES
MONOCLINIC LATTICES
NEOPLASMS
PHOSPHORUS 21
PHOSPHORYLATION
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Summary: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{sub 1}, a vacuolar type H{sup +}-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{sub 1} induced G{sub 0}/G{sub 1} cell cycle arrest and apoptosis which were accompanied by the down-regulation of cyclin D{sub 1} and cyclin E, the up-regulation of p21{sup Cip1} as well as cleavages of caspases-3, -7, -8, and -9 and PARP. Further investigation revealed that bafilomycin A{sub 1} increased the phosphorylation of ERK, JNK, and p38. In this regard, p38 inhibitor partially reversed the anti-proliferative effect of bafilomycin A{sub 1}. To conclude, inhibition of macroautophagy by bafilomycin A{sub 1} lowers G{sub 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.
ISSN:0006-291X
1090-2104
DOI:10.1016/J.BBRC.2009.03.051