Bortezomib enhances cancer cell death by blocking the autophagic flux through stimulating ERK phosphorylation.
Bortezomib enhances cancer cell death by blocking the autophagic flux through stimulating ERK phosphorylation.
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DOI：
10.1038/cddis.2014.468
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发表时间：
2014-11-06
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
26S蛋白酶体硼替佐米抑制剂（Velcade）的抗肿瘤活性已被观察到用于多种恶性肿瘤，包括结肠癌、前列腺癌、乳腺癌和卵巢癌。硼替佐米被认为可以刺激自噬，但科学观察并不总是支持这一观点。ERK活性和自噬之间的相互作用是复杂的，并不完全清楚。自噬蛋白最近被证明可以调节ERK的功能，而ERK的激活也被发现可以诱导自噬。另一方面，ERK的持续激活也被证明可以抑制自噬过程的成熟步骤。在这项研究中，我们试图确定硼替佐米治疗癌细胞的自噬调节机制。结果表明，硼替佐米阻断了自噬通量，但不抑制自噬体和溶酶体的融合。在卵巢癌、子宫内膜癌和肝癌细胞中，硼替佐米通过抑制组织蛋白酶抑制溶酶体中的蛋白质降解，这需要ERK磷酸化的参与，而不需要JNK或p38的参与。我们发现ERK磷酸化降低了组织蛋白酶，进一步解释了ERK磷酸化如何抑制自噬通量。综上所述，硼替佐米可能诱导ERK磷酸化抑制组织蛋白酶B，抑制卵巢癌和其他实体肿瘤自噬的催化过程。硼替佐米抑制顺铂诱导的自噬可提高卵巢癌化疗疗效。正如我们还发现硼替佐米阻断其他癌症的自噬通量，硼替佐米通过消除化疗相关的自噬而产生的协同细胞毒作用可能有助于我们制定多种癌症的联合治疗策略。
The antitumor activity of an inhibitor of 26S proteasome bortezomib (Velcade) has been observed in various malignancies, including colon cancer, prostate cancer, breast cancer, and ovarian cancer. Bortezomib has been proposed to stimulate autophagy, but scientific observations did not always support this. Interactions between ERK activity and autophagy are complex and not completely clear. Autophagy proteins have recently been shown to regulate the functions of ERK, and ERK activation has been found to induce autophagy. On the other hand, sustained activation of ERK has also been shown to inhibit the maturation step of the autophagy process. In this study, we sought to identify the mechanism of autophagy regulation in cancer cells treated with bortezomib. Our results indicate that bortezomib blocked the autophagic flux without inhibiting the fusion of the autophagosome and lysosome. In ovarian cancer, as well as endometrial cancer and hepatocellular carcinoma cells, bortezomib inhibited protein degradation in lysosomes by suppressing cathepsins, which requires the participation of ERK phosphorylation, but not JNK or p38. Our findings that ERK phosphorylation reduced cathepsins further explain how ERK phosphorylation inhibits the autophagic flux. In conclusion, bortezomib may induce ERK phosphorylation to suppress cathepsin B and inhibit the catalytic process of autophagy in ovarian cancer and other solid tumors. The inhibition of cisplatin-induced autophagy by bortezomib can enhance chemotherapy efficacy in ovarian cancer. As we also found that bortezomib blocks the autophagic flux in other cancers, the synergistic cytotoxic effect of bortezomib by abolishing chemotherapy-related autophagy may help us develop strategies of combination therapies for multiple cancers.
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DOI：
10.1038/nrclinonc.2013.5
发表时间：
2013-04
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
通讯作者：
--
影响因子：
9
作者：
Kao, C.;Chao, A.;Tsai, C. L.;Lin, C. Y.;Chuang, W. C.;Chen, H. W.;Yen, T. C.;Wang, T. H.;Lai, C. H.;Wang, H. S.
通讯作者：
Wang, H. S.
影响因子：
8
作者：
Chao, A.;Lin, C-Y;Lai, C-H
通讯作者：
Lai, C-H
影响因子：
4.7
作者：
Befani, Christina D.;Vlachostergios, Panagiotis J.;Liakos, Panagiotis
通讯作者：
Liakos, Panagiotis
影响因子：
13.3
作者：
Dalby KN;Tekedereli I;Lopez-Berestein G;Ozpolat B
通讯作者：
Ozpolat B