LAUSR

The endoplasmic reticulum (ER) contributes to various protein modifications such as protein folding. Also, the ER-associated degradation (ERAD) complex removes defective proteins, which prevents the accumulation of misfolded proteins to avoid abnormality of physiological activity. Several physiological and pathological stimuli, such as hypoxia and nutrient starvation lead to unfolded protein responses (UPRs). Given that hyper-proliferation causes hypoxia and glucose shortening, cancer cells might induce UPRs resulting in misfolded protein accumulation and aggregation. Although the ERAD complex removes defective proteins, the capacity of the proteasomal degradation pathway is not enough to completely clear defective proteins in hyper-proliferative cancer cells. Thus, it is likely that cancer cells require additional misfolded protein degradation systems. Transmembrane protein 9 (TMEM9) has been identified as a vesicular acidification amplifier, which is upregulated in cancer cells for Wnt/β-catenin signaling activation via lysosomal protein degradation. In this study, TMEM9 downregulated ER stress-induced misfolded proteins that decrease cancer cell proliferation and viability. ERAD inhibitor declined cancer cell proliferation, reverted by TMEM9. Intriguingly, TMEM9 decreased ERAD-induced apoptosis instead of promoted autophagic cell death under glucose shorten conditions. Here we suggest that lysosomal protein degradation is an additional protein degradation system for the removal of defective proteins and contributes to stable cancer cell proliferation via the clearing of garbage proteins. Citation Format: Dong-Han Wi, Su-Rin Jung, Seong-Ju Lee, Ye-seul Jeon, Youn-Sang Jung, Jae-Il Park. TMEM9 decreases ER stress-induced misfolded proteins via lysosomal protein degradation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4815.