Li Yi, Wu Xiaowei, Li Lin, Liu Yongshuo, Xu Chengshan, Su Dan, Liu Zhihua
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Institute & Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Collaborative Innovation Center for Cancer Medicine, Beijing 100021, PR China.
State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Institute & Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Collaborative Innovation Center for Cancer Medicine, Beijing 100021, PR China.
Cancer Lett. 2017 Sep 28;404:44-52. doi: 10.1016/j.canlet.2017.07.004. Epub 2017 Jul 15.
Apoptosis resistance is an acquired hallmark of cancer cells and many factors can contribute to the tumor cell apoptosis resistance. In this study, we demonstrated that HECTD3, overexpressed in human esophageal squamous cell carcinoma (ESCC), confers cells resistance to cisplatin-induced apoptosis and promotes cancer cell survival. HECTD3 can bind and ubiquitinate caspase-9, which leads to inhibiting caspase-9 oligomerization and association with Apaf-1, and results in suppressing caspase-9 activation and inhibiting apoptosis. Furthermore, this antiapoptotic function of HECTD3 is dependent on its Thr-157 phosphorylation by ERK. HECTD3, but not T157A mutant, facilitates cell survival in ESCC cells in survival assay in vitro and promotes tumor growth in a xenograft mouse model in vivo. These findings establish a new mechanism of cancer cell resistance to apoptosis and provide a new potential strategy for ESCC treatment.
凋亡抗性是癌细胞获得性的特征，许多因素可导致肿瘤细胞的凋亡抗性。在本研究中，我们证明了在人食管鳞状细胞癌（ESCC）中过表达的HECTD3赋予细胞对顺铂诱导凋亡的抗性，并促进癌细胞存活。HECTD3可结合并泛素化半胱天冬酶-9，导致抑制半胱天冬酶-9寡聚化以及与凋亡蛋白酶激活因子-1的结合，从而抑制半胱天冬酶-9激活并抑制凋亡。此外，HECTD3的这种抗凋亡功能依赖于ERK对其苏氨酸-157的磷酸化。在体外存活分析中，HECTD3而非T157A突变体促进ESCC细胞的存活，并在体内异种移植小鼠模型中促进肿瘤生长。这些发现确立了癌细胞抗凋亡的新机制，并为ESCC治疗提供了新的潜在策略。
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