A novel role of lysophosphatidic acid (LPA) in human myeloma resistance to proteasome inhibitors

Pan Su, Liuling Xiao, Lingqun Ye, Zhuo Wang, Wei Xiong, Qiang Wang, Xingzhe Ma, Miao Xian, Maojie Yang, Youli Zu, Sai Ravi Pingali, Jianfei Qian, Qing Yi

Research output: Contribution to journalLetterpeer-review

Abstract

Lysophosphatidic acid (LPA) is a naturally occurring phospholipid that regulates cell proliferation, survival, and migration. However, its role on human multiple myeloma (MM) cells is largely unknown. In this study, we show that LPA, which is highly elevated in MM patients, plays an important role in protecting human MM cells against proteasome inhibitor (PI)-induced apoptosis. LPA bound to its receptor LPAR2 activated its downstream MEK1/2-ERK1/2 signaling pathway and enhanced oxidative phosphorylation (OXPHOS) in mitochondria in MM cells. Increased OXPHOS activity produced more NAD+ and ATP, reduced proteasome activity, and enhanced protein folding and refolding in endoplasmic reticulum (ER), leading to induction of MM resistance to PIs. Importantly, inhibiting LPAR2 activity or knocking out LPAR2 in MM cells significantly enhanced MM sensitivity to PI-induced apoptosis in vitro and in vivo. Interestingly, primary MM cells from LPA-high patients were more resistant to PI-induced apoptosis than MM cells from LPA-low patients. Thus, our study indicates that LPA-LPAR2-mediated signaling pathways play an important role in MM sensitivity to PIs and targeting LPA or LPAR2 may potentially be used to (re)sensitize patients to PI-based therapy.

Original languageEnglish (US)
Article number55
JournalJournal of Hematology and Oncology
Volume15
Issue number1
DOIs
StatePublished - Dec 2022

Keywords

  • Drug resistance
  • LPA
  • LPAR2
  • Multiple myeloma
  • Proteasome inhibitor

ASJC Scopus subject areas

  • Hematology
  • Molecular Biology
  • Oncology
  • Cancer Research

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