Involvement of caspase-9 in autophagy-mediated cell survival pathway
Involvement of caspase-9 in autophagy-mediated cell survival pathway
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DOI：
10.1016/j.bbamcr.2010.09.016
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发表时间：
2011-01-01
影响因子：
5.1
通讯作者：
Cho, Ssang-Goo
中科院分区：
文献类型：
--
作者：
Jeong, Hyo-Soon;Choi, Hye Yeon;Cho, Ssang-Goo
非甾体类抗炎药（NSAIDs）已被认为可用于预防和治疗恶性肿瘤。FR122047 （FR）已知具有抗炎作用，但该化学物质的抗癌活性尚未确定。在本研究中，我们发现用FR治疗乳腺癌MCF-7细胞导致凋亡，并伴有明显的caspase激活。caspase特异性抑制剂的治疗表明，fr诱导的细胞凋亡是caspase-8依赖性的，caspase-9活性的抑制导致了意想不到的、显著的细胞死亡增强。通过特异性siRNA敲低caspase-9的表达会增加对fr诱导的细胞死亡的易感性，这与caspase-9抑制剂处理的结果一致。抑制caspase-9通过调节溶酶体pH值和酸依赖性组织蛋白酶活性来阻断自噬过程，并通过阻断细胞保护性自噬而增加细胞死亡。MCF-7细胞经自噬诱导药物萝卜硫素处理后，LC3-II也明显积累，与caspase-9抑制剂共同处理后，对萝卜硫素诱导的细胞死亡的易感性增加。与FR或萝卜硫素组不同，与caspase-9抑制剂共同处理时，etopo苷或阿霉素诱导的细胞死亡被抑制，药物未能诱导MCF-7细胞显著自噬。综上所述，我们的数据最初表明，抑制caspase-9可能会阻断自噬通量，并由于细胞保护性自噬的阻断而增加细胞死亡。(c) 2010 Elsevier B.V.保留所有权利。
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered for use in the prevention and treatment of cancer malignancy. FR122047 (FR) is known to have an anti-inflammatory effect, but the anticancer activity of the chemical has not yet been identified. In the present study, we could find that treatment of breast cancer MCF-7 cells with FR led to apoptosis accompanying with apparent activation of caspases. Treatment of caspase-specific inhibitors revealed that FR-induced apoptosis was caspase-8-dependent and inhibition of caspase-9 activity resulted in unexpected, marked enhancement of cell death. Knockdown of caspase-9 expression by specific siRNA caused increased susceptibility to FR-induced cell death, consistent with the results obtained with treatment of caspase-9 inhibitor. Inhibition of caspase-9 blocked the autophagic process by modulating lysosomal pH and acid-dependent cathepsin activities and augmented cell death due to blockage of cytoprotective autophagy. MCF-7 cells treated with sulforaphane, an autophagy-inducing drug, also showed marked accumulation of LC3-II, and co-treatment with caspase-9 inhibitor brought about increased susceptibility to sulforaphane-induced cell death. Different from the cases with FR or sulforaphane, etoposide- or doxorubicin-induced cell death was suppressed with co-treatment of caspase-9 inhibitor, and the drugs failed to induce significant autophagy in MCF-7 cells. Taken together, our data originally suggest that inhibition of caspase-9 may block the autophagic flux and enhance cell death due to blockage of cytoprotective autophagy. (c) 2010 Elsevier B.V. All rights reserved.