LPA receptor 1 (LPAR1) is a novel interaction partner of Filamin A that promotes Filamin A phosphorylation, MRTF-A transcriptional activity and oncogene-induced senescence

Abstract

Myocardin-related transcription factors A and B (MRTFs) are coactivators of Serum Response Factor (SRF), which controls fundamental biological processes such as cell growth, migration, and differentiation. MRTF and SRF transcriptional activity play an important role in hepatocellular carcinoma (HCC) growth, which represents the second leading cause of cancer-related mortality in humans worldwide. We, therefore, searched for druggable targets in HCC that regulate MRTF/SRF transcriptional activity and can be exploited therapeutically for HCC therapy. We identified the G protein-coupled lysophosphatidic acid receptor 1 (LPAR1) as a novel interaction partner of MRTF-A and Filamin A (FLNA) using fluorescence resonance energy transfer-(FRET) and proximity ligation assay (PLA) in vitro in HCC cells and in vivo in organoids. We found that LPAR1 promotes FLNA phosphorylation at S2152 which enhances the complex formation of FLNA and MRTF-A, actin polymerization, and MRTF transcriptional activity. Pharmacological blockade or depletion of LPAR1 prevents FLNA phosphorylation and complex formation with MRTF-A, resulting in reduced MRTF/SRF target gene expression and oncogene-induced senescence. Thus, inhibition of the LPAR1–FLNA–MRTF-A interaction represents a promising strategy for HCC therapy.

The Emerging Role of LPA as an Oncometabolite

“…Another strategy to intervene with LPA signalling in tumours is to block the activation of LPARs. Blocking LPAR1 with Ki-16425 in hepatocellular carcinoma interrupts the LPAR1/MRTF-A/filamin A complex-as discussed above-and leads to oncogeneinduced senescence [151]. Ki-16425 is also able to block T-cell lymphoma growth both in vitro and in vivo by inhibiting glycolysis, inducing apoptosis and activating the immune system [161].…”

“…The role of LPA in cancer-related pain is showcased in fibrosarcoma, where exosomal LPA through LPARs induces cancerrelated pain by sensitising C-fibre nociceptors [150]. LPA also affects senescence, as in hepatocellular carcinoma, LPA activates LPAR1, which interacts with myocardin-related transcription factor A (MRTF-A) and filamin A to trigger actin polymerisation and protect against oncogene-induced senescence [151]. In gastric cancer cells, LPA-induced LPAR2 activation promotes β-catenin nuclear localisation through modulation of glycogen synthase kinase-3β (GSK-3β).…”

Mechanical homeostasis imbalance in hepatic stellate cells activation and hepatic fibrosis

“…Myocardin-related transcription factors (MRTFs) are mechanosensory that link actin dynamics, including MRTF-A and MRTF-B, the former interacting primarily with serum response factor (SRF) in the nucleus and subsequently activating target gene transcription ( Konopa et al, 2022 ). MRTF-A (also known as MKL-1) binds to G-actin and is sequestered in the cytoplasm, then shuttles from the cytoplasm to the nucleus, which is controlled by actin polymerization mediated by the RhoA-ROCK pathway ( Rahman et al, 2018 ; Solagna et al, 2020 ).…”