TY - JOUR
T1 - A novel role of lysophosphatidic acid (LPA) in human myeloma resistance to proteasome inhibitors
AU - Su, Pan
AU - Xiao, Liuling
AU - Ye, Lingqun
AU - Wang, Zhuo
AU - Xiong, Wei
AU - Wang, Qiang
AU - Ma, Xingzhe
AU - Xian, Miao
AU - Yang, Maojie
AU - Zu, Youli
AU - Pingali, Sai Ravi
AU - Qian, Jianfei
AU - Yi, Qing
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/5/7
Y1 - 2022/5/7
N2 - 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.
AB - 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.
KW - Drug resistance
KW - LPA
KW - LPAR2
KW - Multiple myeloma
KW - Proteasome inhibitor
KW - Humans
KW - Multiple Myeloma/drug therapy
KW - Proteasome Inhibitors
KW - Apoptosis
KW - Lysophospholipids/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85129746799&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129746799&partnerID=8YFLogxK
U2 - 10.1186/s13045-022-01269-5
DO - 10.1186/s13045-022-01269-5
M3 - Article
C2 - 35526043
AN - SCOPUS:85129746799
SN - 1756-8722
VL - 15
SP - 55
JO - Journal of Hematology and Oncology
JF - Journal of Hematology and Oncology
IS - 1
M1 - 55
ER -