The STAT3 inhibitor stattic overcome bortezomib-resistance in multiple myeloma via decreasing PSMB6

Exp Cell Res. 2023 Aug 1;429(1):113634. doi: 10.1016/j.yexcr.2023.113634. Epub 2023 May 18.

Abstract

Bortezomib, an FDA approved drug in 2003 for newly diagnosed and relapsed/refractory MM, had showed great efficacy in different clinical settings. However, many patients still developed resistance to Bortezomib, and the mechanism of action remains unelucidated. Here, we showed that Bortezomib resistance can be partially overcome by targeting a different subunit of 20 S complex - PSMB6. PSMB6 knock down by shRNA increased sensitivity to Bortezomib in resistant and sensitive cell line. Interestingly, a STAT3 inhibitor, Stattic, is shown to selectively inhibit PSMB6 and induce apoptosis in Bortezomib resistant and sensitive MM cells, even with IL-6 induction. Therefore, PSMB6 is a novel target for Bortezomib resistance and Stattic may offer a potential therapeutic strategy.

Keywords: Bortezomib-resistance; Multiple myeloma; PSMB6; STAT3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Apoptosis / genetics
  • Bortezomib / pharmacology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics
  • Humans
  • Multiple Myeloma* / drug therapy
  • Multiple Myeloma* / genetics
  • Multiple Myeloma* / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism

Substances

  • Bortezomib
  • Antineoplastic Agents
  • stattic
  • STAT3 protein, human
  • STAT3 Transcription Factor