Inhibition of macroautophagy by bafilomycin A1 lowers proliferation and induces apoptosis in colon cancer cells
Inhibition of macroautophagy by bafilomycin A1 lowers proliferation and induces apoptosis in colon cancer cells
复制标题
DOI：
10.1016/j.bbrc.2009.03.051
复制
发表时间：
2009-05-01
影响因子：
3.1
通讯作者：
Cho, Chi Hin
中科院分区：
文献类型：
--
作者：
Wu, Ya Chun;Wu, William Ka Kei;Cho, Chi Hin
大自噬是细胞质内容物和细胞器被双膜结合囊泡隔离并随后递送到溶酶体进行降解的过程。大自噬是蛋白质降解的主要细胞内途径，也是应激时产生营养物质的促生存机制。在本研究中，巴弗洛霉素A（1）是一种空泡型H+-ATP酶抑制剂，通过阻止结肠癌细胞中溶酶体的酸化来抑制大自噬。未降解的LC 3蛋白的积累证明了减少的大自噬。巴弗洛霉素A（1）抑制巨自噬可诱导G 0/G1期细胞阻滞和凋亡，并伴有cyclin D、cyclin E表达下调，p21（Cip 1）表达上调，caspase-3、-7、-8、-9和PARP裂解。进一步的研究表明，巴弗洛霉素A（1）增加ERK，JNK和p38的磷酸化。在这方面，p38抑制剂部分逆转了巴弗洛霉素A的抗增殖作用（1）。综上所述，巴菲洛霉素A（1）抑制大自噬降低了结肠癌细胞的G（1）-S转换并诱导了细胞凋亡。我们的研究结果不仅表明巨自噬抑制剂可用于治疗以抑制癌症生长，而且还描绘了巨自噬和细胞凋亡之间的关系。(C)2009 Elsevier Inc. All rights reserved.
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, 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 bafilornycin 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. (C) 2009 Elsevier Inc. All rights reserved.