PDF(Pubmed)
Abstract：
Tumor necrosis factor superfamily (TNFSF) resistance contributes to the development and progression of tumors and resistance to various cancer therapies. Tumor-intrinsic alterations involved in the adaptation to the TNFSF response remain largely unknown. Here, we demonstrate that protein kinase C substrate 80K-H (PRKCSH) abundance in lung cancers boosts oncogenic IGF1R activation, leading to TNFSF resistance. PRKCSH abundance is correlated with IGF1R upregulation in lung cancer tissues. Specifically, PRKCSH interacts with IGF1R and extends its half-life. The PRKCSH-IGF1R axis in tumor cells impairs caspase-8 activation, increases Mcl-1 expression, and inhibits caspase-9, leading to an imbalance between cell death and survival. PRKCSH deficiency augmented the antitumor effects of natural killer (NK) cells, representative TNFSF effector cells, in a tumor xenograft IL-2Rg-deficient NOD/SCID (NIG) mouse model. Our data suggest that PRKCSH plays a critical role in TNFSF resistance and may be a potential target to improve the efficacy of NK cell-based cancer therapy.
摘要：
肿瘤坏死因子超家族(TNFSF)抗性有助于肿瘤的发展和进展以及对各种癌症疗法的抗性。涉及对TNFSF应答的适应的肿瘤固有改变在很大程度上仍然未知。这里,我们证明了肺癌中蛋白激酶C底物80K-H（PRKCSH）的丰度促进了致癌IGF1R的激活，导致TNFSF抵抗。肺癌组织中PRKCSH丰度与IGF1R上调相关。具体来说,PRKCSH与IGF1R相互作用并延长其半衰期。肿瘤细胞中的PRKCSH-IGF1R轴损害caspase-8的激活，增加Mcl-1表达，并抑制caspase-9，导致细胞死亡和存活之间的不平衡。PRKCSH缺乏增强了自然杀伤（NK）细胞的抗肿瘤作用，代表性TNFSF效应细胞，在肿瘤异种移植IL-2Rg缺陷型NOD/SCID(NIG)小鼠模型中。我们的数据表明，PRKCSH在TNFSF耐药中起着至关重要的作用，并且可能是提高基于NK细胞的癌症治疗效果的潜在靶标。
