Downregulation of PA28 alpha induces proteasome remodeling and results in resistance to proteasome inhibitors in multiple myeloma

• Type of Material: Article
• Authors: Yanyan Gu, Emory University; Benjamin G. Barwick, Emory University; Mala Shanmugam, Emory University; Craig Hofmeister, Emory University; Jonathan Kaufman, Emory University; Ajay Nooka, Emory University; Vikas Gupta, Emory University; Madhav Dhodapkar, Emory University; Lawrence Boise, Emory University; Sagar Lonial, Emory University
• Language: English
• Date: 2020-12-14
• Publisher: SPRINGERNATURE
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41408-020-00393-0
• Title of Journal or Parent Work: BLOOD CANCER JOURNAL
• Volume: 10
• Issue: 12
• Start Page: 125
• End Page: 125
• Grant/Funding Information: The work is supported by Takeda and Celgene to S.L. Y.G. is supported by Research Fellow Award from the Multiple Myeloma Research Foundation (MMRF). B.G.B. is supported by Developmental Funds from the Winship Cancer Institute of Emory University, post-doctoral fellowship PF-17-109-1-TBG from the American Cancer Society, and a Research Scholar Fellow Award from the Multiple Myeloma Research Foundation (MMRF).
• Keywords: PA28; Oncology; BETA; Hematology; ALPHA; Science & Technology; SENSITIVITY; PROTEIN ACTIVATOR; EXPRESSION; BORTEZOMIB; SUBUNITS; CELLS; PATHWAY; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Oncology; Biology, Cell; Health Sciences, Medicine and Surgery

Abstract

Protein homeostasis is critical for maintaining eukaryotic cell function as well as responses to intrinsic and extrinsic stress. The proteasome is a major portion of the proteolytic machinery in mammalian cells and plays an important role in protein homeostasis. Multiple myeloma (MM) is a plasma cell malignancy with high production of immunoglobulins and is especially sensitive to treatments that impact protein catabolism. Therapeutic agents such as proteasome inhibitors have demonstrated significant benefit for myeloma patients in all treatment phases. Here, we demonstrate that the 11S proteasome activator PA28α is upregulated in MM cells and is key for myeloma cell growth and proliferation. PA28α also regulates MM cell sensitivity to proteasome inhibitors. Downregulation of PA28α inhibits both proteasomal load and activity, resulting in a change in protein homeostasis less dependent on the proteasome and leads to cell resistance to proteasome inhibitors. Thus, our findings suggest an important role of PA28α in MM biology, and also provides a new approach for targeting the ubiquitin-proteasome system and ultimately sensitivity to proteasome inhibitors.