HSPA5 negatively regulates lysosomal activity through ubiquitination of MUL1 in head and neck cancer
HSPA5 negatively regulates lysosomal activity through ubiquitination of MUL1 in head and neck cancer
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DOI：
10.1080/15548627.2017.1414126
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发表时间：
2018-01-01
期刊：
影响因子：
13.3
通讯作者：
Kim, Chul-Ho
中科院分区：
文献类型：
--
作者：
Kim, Sun-Yong;Kim, Hyo Jeong;Kim, Chul-Ho
HSPA 5/GRP 78/BiP在细胞存活或肿瘤进展中起重要作用。由于这些原因，HSPA 5是癌症发展中的新兴治疗靶点。在这里，我们报告说，HSPA 5有助于头颈癌（HNC）生存通过维持溶酶体活性，然而，非热等离子体（NTP，被认为是下一代癌症治疗）处理的解决方案（NTS）抑制HNC进展通过HSPA 5依赖性改变溶酶体活性。HSPA 5通过溶酶体相关蛋白或基因表达的调节来防止NTS诱导的溶酶体抑制。然而，NTS诱导的MUL 1/MULAN/GIDE/MAPL（NF κ B 1的线粒体泛素连接酶激活剂）通过K48连接的赖氨酸446（K446）残基处的泛素化导致HSPA 5的下调。MUL 1敲低通过减少HNC细胞中的HSPA 5泛素化来阻碍NTS诱导的溶酶体抑制或细胞毒性。当MUL 1被抑制时，HNC患者的组织中HSPA 5过表达。NTS通过在异种移植模型中改变MUL 1和HSPA 5的表达强烈抑制HNC进展。然而，NTS在通过CRISPR/Cas9系统产生的MUL 1敲除（KO）HNC细胞中不诱导肿瘤进展的抑制或HSPA 5减少。这些数据提供了令人信服的证据来支持MUL 1-HSPA 5轴的调节可以是治疗HNC的新策略的想法。
HSPA5/GRP78/BiP plays an important role in cell survival or tumor progression. For these reasons, HSPA5 is an emerging therapeutic target in cancer development. Here we report that HSPA5 contributes to head and neck cancer (HNC) survival via maintenance of lysosomal activity; however, a nonthermal plasma (NTP, considered as a next-generation cancer therapy)-treated solution (NTS) inhibits HNC progression through HSPA5-dependent alteration of lysosomal activity. HSPA5 prevents NTS-induced lysosome inhibition through lysosomal-related proteins or regulation of gene expression. However, NTS-induced MUL1/MULAN/GIDE/MAPL (mitochondrial ubiquitin ligase activator of NFKB 1) leads to downregulation of HSPA5 via K48-linked ubiquitination at the lysine 446 (K446) residue. MUL1 knockdown hinders NTS-induced lysosome inhibition or cytotoxicity through the reduction of HSPA5 ubiquitination in HNC cells. While MUL1 was suppressed, HSPA5 was overexpressed in tissues of HNC patients. NTS strongly inhibited HNC progression via alterations of expression of MUL1 and HSPA5, in vivo in a xenograft model. However, NTS did not induce inhibition of tumor progression or HSPA5 reduction in MUL1 knockout (KO) HNC cells which were generated by CRISPR/Cas9 system. The data provide compelling evidence to support the idea that the regulation of the MUL1-HSPA5 axis can be a novel strategy for the treatment of HNC.