Regulation of anti-apoptotic Bcl-2 family protein Mcl-1 by S6 kinase 2.
Regulation of anti-apoptotic Bcl-2 family protein Mcl-1 by S6 kinase 2.
复制标题
DOI：
10.1371/journal.pone.0173854
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Sridharan S
中科院分区：
文献类型：
--
作者：
Basu A;Sridharan S
抗凋亡Bcl-2家族蛋白髓样细胞白血病-1（Mcl-1）在乳腺癌细胞存活和化疗耐药性中起重要作用。我们以前已经表明，敲低40 S核糖体蛋白S6激酶-2（S6 K2），其作用于雷帕霉素复合物1（mTORC 1）的机制靶点下游，通过凋亡刺激增强乳腺癌细胞死亡。S6 K2耗竭导致的细胞死亡增加部分是由于Akt失活。在本研究中，我们研究了S6 K2是否调节Akt下游的Mcl-1。沉默T47 D细胞中S6 K2而非S6 K1可降低Mcl-1水平，并增强TRAIL和阿霉素诱导的细胞凋亡。S6 K2的敲低也降低了抗凋亡Bcl-xl的水平。耗尽的肿瘤抑制蛋白PDCD 4（程序性细胞死亡4），它调节翻译的几种抗凋亡蛋白，逆转下调Bcl-xl，但不是Mcl-1，并未能逆转的影响，S6 K2敲低多柔比星诱导的细胞凋亡的增强。通过S6 K2敲低下调的Mcl-1被蛋白酶体抑制剂MG 132部分恢复。过表达具有催化活性的Akt或敲低Akt的底物糖原合成酶激酶-3（GSK 3）-β对S6 K2缺陷引起的Mcl-1下调几乎没有影响。沉默S6 K2增加了c-Jun N-末端激酶（JNK）的水平，敲低JNK 1增加了基础Mcl-1水平，并部分逆转了敲低S6 K2对Mcl-1下调的影响。JNK 1敲低也有适度的影响，在减少增加阿霉素诱导的细胞凋亡引起的S6 K2缺陷。这些结果表明，S6 K2通过多种机制调节细胞凋亡，并涉及Akt和JNK。
The anti-apoptotic Bcl-2 family protein myeloid cell leukemia-1 (Mcl-1) plays an important role in breast cancer cell survival and chemoresistance. We have previously shown that knockdown of the 40S ribosomal protein S6 kinase-2 (S6K2), which acts downstream of the mechanistic target of rapamycin complex 1 (mTORC1), enhanced breast cancer cell death by apoptotic stimuli. The increase in cell death by S6K2 depletion was partly due to inactivation of Akt. In the present study, we investigated if S6K2 regulates Mcl-1, which acts downstream of Akt. Silencing of S6K2 but not S6K1 in T47D cells decreased Mcl-1 level, and potentiated apoptosis induced by TRAIL and doxorubicin. Knockdown of S6K2 also decreased the level of anti-apoptotic Bcl-xl. Depletion of the tumor suppressor protein PDCD4 (programmed cell death 4), which regulates translation of several anti-apoptotic proteins, reversed downregulation of Bcl-xl but not Mcl-1 and failed to reverse the effect of S6K2 knockdown on potentiation of doxorubicin-induced apoptosis. Downregulation of Mcl-1 by S6K2 knockdown was partly restored by the proteasome inhibitor MG132. Overexpression of catalytically-active Akt or knockdown of glycogen synthase kinase-3 (GSK3)-β, a substrate for Akt, had little effect on Mcl-1 downregulation caused by S6K2 deficiency. Silencing of S6K2 increased the level of c-Jun N-terminal kinase (JNK) and knockdown of JNK1 increased basal Mcl-1 level and partly reversed the effect of S6K2 knockdown on Mcl-1 downregulation. JNK1 knockdown also had a modest effect in attenuating the increase in doxorubicin-induced apoptosis caused by S6K2 deficiency. These results suggest that S6K2 regulates apoptosis via multiple mechanisms, and involves both Akt and JNK.