PRKCSH contributes to TNFSF resistance by extending IGF1R half-life and activation in lung cancer

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. PRKCSH: a potential game-changer in lung cancer resistance Cancer cells often develop resistance to treatments that stimulate the natural cell death process, including immune therapies that initiate a group of proteins known as tumour necrosis factors (TNFs - proteins that can cause cell death). Researchers at Sungkyunkwan University in South Korea have discovered that a protein named PRKCSH is vital in assisting lung cancer cells to resist TNFs. Through a sequence of lab tests, they found that PRKCSH extends the lifespan of another protein, IGF1R, which subsequently prevents the activation of proteins that start cell death. When PRKCSH was reduced, cancer cells became more susceptible to TNFs and were more effectively eliminated by immune cells known as natural killer cells. These results suggest that focusing on PRKCSH could help overcome resistance to TNF-based cancer treatments. “This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.” not present in xml.