Lee, Hong-Jae Lee, Dong-Min Seo, Min-Ji Kang, Ho-Chul Kwon, Seok-Kyu Choi, Kyeong-Sook 2024-01-19T12:32:14Z 2024-01-19T12:32:14Z 2022-04-03 2022-03 1661-6596 https://pubs.kist.re.kr/handle/201004/115572 PSMD14, a subunit of the 19S regulatory particles of the 26S proteasome, was recently identified as a potential prognostic marker and therapeutic target in diverse human cancers. Here, we show that the silencing and pharmacological blockade of PSMD14 in MDA-MB 435S breast cancer cells induce paraptosis, a non-apoptotic cell death mode characterized by extensive vacuolation derived from the endoplasmic reticulum (ER) and mitochondria. The PSMD14 inhibitor, capzimin (CZM), inhibits proteasome activity but differs from the 20S proteasome subunit-inhibiting bortezomib (Bz) in that it does not induce aggresome formation or Nrf1 upregulation, which underlie Bz resistance in cancer cells. In addition to proteasome inhibition, the release of Ca2+ from the ER into the cytosol critically contributes to CZM-induced paraptosis. Induction of paraptosis by targeting PSMD14 may provide an attractive therapeutic strategy against cancer cells resistant to proteasome inhibitors or pro-apoptotic drugs. English Multidisciplinary Digital Publishing Institute (MDPI) PSMD14 Targeting Triggers Paraptosis in Breast Cancer Cells by Inducing Proteasome Inhibition and Ca2+ Imbalance Article 10.3390/ijms23052648 1 International Journal of Molecular Sciences, v.23, no.5 International Journal of Molecular Sciences 23 5 Y scie scopus 000771432600001 2-s2.0-85125376510 Biochemistry & Molecular Biology Chemistry, Multidisciplinary Biochemistry & Molecular Biology Chemistry Article ENDOPLASMIC-RETICULUM BORTEZOMIB DEGRADATION METASTASIS CARCINOMA UBIQUITIN SNAIL PSMD14 paraptosis proteasome proteostasis Ca2+ imbalance