PSMD14 Targeting Triggers Paraptosis in Breast Cancer Cells by Inducing Proteasome Inhibition and Ca2+ Imbalance.

Hong-Jae Lee,Seok-Kyu Kwon,Kyeong-Sook Choi,Dong-Min Lee,Min-Ji Seo,Ho-Chul Kang

doi:10.3390/ijms23052648

Abstract

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.

Highlights

The 26S proteasome consists of a 20S proteolytic core particle (CP) and one or two19S regulatory particles (RPs)
The targeting of proteasome 20S peptidase activity with Bz and carfilzomib has revolutionized the treatment of MM, but not all patients respond to these compounds, and those who do eventually suffer a relapse
We show that targeting PSMD14 may evade the mechanisms through which cancer cells acquire resistance to Bz, a proteasome inhibitors (PIs) targeting 20S proteasome CP, such as the aggresome formation and Nrf1 activation [30,31]

Summary

Introduction

The 26S proteasome consists of a 20S proteolytic core particle (CP) and one or two19S regulatory particles (RPs). The proteasome inhibitors (PIs) that target 20S proteolytic CP activity, such as bortezomib (Bz) and carfilzomib, offer effective therapy for multiple myeloma (MM) patients [1,2], drug resistance often emerges, and the clinical efficacy of Bz as a single agent is limited in solid tumors [3,4]. This study shows that Nrf activation and aggresome formation, which underlie the PI resistance mechanisms of cancer cells, are not induced by PSMD14 inhibition. We found that both proteasome inhibition and intracellular Ca2+ imbalance critically contribute to the paraptosis induced by PSMD14 inhibition in breast cancer cells. Induction of paraptosis by targeting PSMD14 may offer a novel therapeutic strategy against cancers that have acquired resistance to PIs or pro-apoptotic drugs

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Conclusion