Mechanism by which Mcl-1 regulates cancer-specific apoptosis triggered by mda-7/IL-24, an IL-10-related cytokine.
Mechanism by which Mcl-1 regulates cancer-specific apoptosis triggered by mda-7/IL-24, an IL-10-related cytokine.
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DOI：
10.1158/0008-5472.can-10-0563
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发表时间：
2010-06-15
期刊：
影响因子：
11.2
通讯作者：
Fisher PB
中科院分区：
文献类型：
--
作者：
Dash R;Richards JE;Su ZZ;Bhutia SK;Azab B;Rahmani M;Dasmahapatra G;Yacoub A;Dent P;Dmitriev IP;Curiel DT;Grant S;Pellecchia M;Reed JC;Sarkar D;Fisher PB
黑色素瘤分化相关基因-7/白细胞介素-24（mda-7/IL-24）是一种属于IL-10家族的细胞因子，通过促进内质网（ER）应激反应选择性地诱导癌细胞凋亡而不损害正常细胞。ER应激反应最终导致细胞死亡的确切分子机制需要进一步阐明。目前的研究表明，在前列腺癌细胞中，mda-7/IL-24诱导的ER应激反应通过抑制抗凋亡蛋白髓样细胞白血病-1（Mcl-1）的翻译而引起细胞凋亡。Mcl-1的强制表达阻断了mda-7/IL-24的致死性，而Mcl-1的RNA干扰或基因敲除显著地使转化细胞对mda-7/IL-24敏感。通过mda-7/IL-24下调Mcl-1可解除其与促凋亡蛋白巴克的结合，导致巴克寡聚化并导致细胞死亡。这些观察结果表明Bcl-2蛋白家族成员Mcl-1在调节这种细胞因子诱导的癌症特异性细胞凋亡中的重要作用。因此，我们的研究提供了进一步的见解ER应激诱导的mda-7/IL-24的癌症选择性凋亡的分子机制。由于Mcl-1在大多数前列腺癌中过表达，mda-7/IL-24可能为这种疾病提供有效的治疗。
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), a cytokine belonging to the IL-10 family, selectively induces apoptosis in cancer cells without harming normal cells by promoting an endoplasmic reticulum (ER) stress response. The precise molecular mechanism by which the ER stress response culminates in cell death requires further clarification. The present study shows that in prostate carcinoma cells, the mda-7/IL-24-induced ER stress response causes apoptosis by translational inhibition of the antiapoptotic protein myeloid cell leukemia-1 (Mcl-1). Forced expression of Mcl-1 blocked mda-7/IL-24 lethality, whereas RNA interference or gene knockout of Mcl-1 markedly sensitized transformed cells to mda-7/IL-24. Mcl-1 downregulation by mda-7/IL-24 relieved its association with the proapoptotic protein Bak, causing oligomerization of Bak and leading to cell death. These observations show the profound role of the Bcl-2 protein family member Mcl-1 in regulating cancer-specific apoptosis induced by this cytokine. Thus, our studies provide further insights into the molecular mechanism of ER stress-induced cancer-selective apoptosis by mda-7/IL-24. As Mcl-1 is overexpressed in the majority of prostate cancers, mda-7/IL-24 might provide an effective therapeutic for this disease.