肿瘤细胞治疗研究
英文原题：PRKCSH contributes to TNFSF resistance by extending IGF1R half-life and activation in lung cancer.
我们的数据表明，PRKCSH 在 TNFSF 耐药中发挥关键作用，并可能成为提高基于 NK 细胞的癌症治疗疗效的潜在靶点。
肿瘤坏死因子超家族（TNFSF）耐药促进肿瘤的发生和进展，并导致对多种癌症治疗的耐药。肿瘤内在的参与适应TNFSF应答的改变在很大程度上仍不清楚。在此，我们证明肺癌中蛋白激酶C底物80K-H（PRKCSH）的丰度增强致癌性IGF1R激活，导致TNFSF耐药。PRKCSH丰度与肺癌组织中IGF1R上调相关。具体而言，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激活，增加Mcl-1表达，并抑制caspase-9，导致细胞死亡与存活之间的失衡。在肿瘤异种移植IL-2Rg缺陷NOD/SCID（NIG）小鼠模型中，PRKCSH缺陷增强了自然杀伤（NK）细胞（代表性的TNFSF效应细胞）的抗肿瘤作用。我们的数据表明，PRKCSH在TNFSF耐药中发挥关键作用，并可能成为提高基于NK细胞的癌症治疗疗效的潜在靶点。
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.
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