Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, TX, USA.
Department of Pathology and Genomic Medicine, Institute for Academic Medicine, Houston Methodist Research Institute, Houston, TX, USA.
J Hematol Oncol. 2022 May 7;15(1):55. doi: 10.1186/s13045-022-01269-5.
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.
溶血磷脂酸（LPA）是一种天然存在的磷脂，可调节细胞增殖、存活和迁移。然而，其在人类多发性骨髓瘤（MM）细胞中的作用在很大程度上尚不清楚。在这项研究中，我们表明，在 MM 患者中高度升高的 LPA 在保护人类 MM 细胞免受蛋白酶体抑制剂（PI）诱导的细胞凋亡中起重要作用。LPA 与受体 LPAR2 结合，激活其下游 MEK1/2-ERK1/2 信号通路，并增强 MM 细胞中线粒体中的氧化磷酸化（OXPHOS）。增加的 OXPHOS 活性产生更多的 NAD 和 ATP，降低蛋白酶体活性，并增强内质网（ER）中的蛋白质折叠和重折叠，从而诱导 MM 对 PI 的耐药性。重要的是，抑制 LPAR2 活性或敲除 MM 细胞中的 LPAR2 可显著增强 MM 对 PI 诱导的细胞凋亡的敏感性，无论是在体外还是体内。有趣的是，来自 LPA 高患者的原代 MM 细胞比来自 LPA 低患者的 MM 细胞对 PI 诱导的细胞凋亡具有更强的抗性。因此，我们的研究表明，LPA-LPAR2 介导的信号通路在 MM 对 PI 的敏感性中起重要作用，靶向 LPA 或 LPAR2 可能潜在地用于使患者对基于 PI 的治疗重新敏感。
