Identification of Heparin-Binding EGF-Like Growth Factor (HB-EGF) as a Biomarker for Lysophosphatidic Acid Receptor Type 1 (LPA1) Activation in Human Breast and Prostate Cancers

Abstract

Lysophosphatidic acid (LPA) is a natural bioactive lipid with growth factor-like functions due to activation of a series of six G protein-coupled receptors (LPA1–6). LPA receptor type 1 (LPA1) signaling influences the pathophysiology of many diseases including cancer, obesity, rheumatoid arthritis, as well as lung, liver and kidney fibrosis. Therefore, LPA1 is an attractive therapeutic target. However, most mammalian cells co-express multiple LPA receptors whose co-activation impairs the validation of target inhibition in patients because of missing LPA receptor-specific biomarkers. LPA1 is known to induce IL-6 and IL-8 secretion, as also do LPA2 and LPA3. In this work, we first determined the LPA induced early-gene expression profile in three unrelated human cancer cell lines expressing different patterns of LPA receptors (PC3: LPA1,2,3,6; MDA-MB-231: LPA1,2; MCF-7: LPA2,6). Among the set of genes upregulated by LPA only in LPA1-expressing cells, we validated by QPCR and ELISA that upregulation of heparin-binding EGF-like growth factor (HB-EGF) was inhibited by LPA1–3 antagonists (Ki16425, Debio0719). Upregulation and downregulation of HB-EGF mRNA was confirmed in vitro in human MDA-B02 breast cancer cells stably overexpressing LPA1 (MDA-B02/LPA1) and downregulated for LPA1 (MDA-B02/shLPA1), respectively. At a clinical level, we quantified the expression of LPA1 and HB-EGF by QPCR in primary tumors of a cohort of 234 breast cancer patients and found a significantly higher expression of HB-EGF in breast tumors expressing high levels of LPA1. We also generated human xenograph prostate tumors in mice injected with PC3 cells and found that a five-day treatment with Ki16425 significantly decreased both HB-EGF mRNA expression at the primary tumor site and circulating human HB-EGF concentrations in serum. All together our results demonstrate that HB-EGF is a new and relevant biomarker with potentially high value in quantifying LPA1 activation state in patients receiving anti-LPA1 therapies.

Lysophosphatidic acid receptor isoforms expression in prostate cancer cells is differentially regulated by the CYP17A1 inhibitor abiraterone and depends on the androgen receptor

“…The LPA receptors' mRNA expression pattern in PC cell lines PC-3 and LNCaP was shown for LPAR1-4. This could be confirmed and extended to LPAR5 and LPAR6 for PC-3 cells, and is in accordance with our data [27,28] . In AR-negative PC-3 cells, LPAR isoforms exhibited no significant differences in LPAR1 to LPAR6 transcripts in the presence and absence of AA.…”

Lysophosphatidic acid activates satellite glia cells and Schwann cells

“…Interestingly, pretreatment with gallein 5 μM similarly attenuated LPA responses in SGCs (Figure d). Finally, the LPA‐induced calcium responses of SGCs were tested in the presence of Ki16425 2 μM, which competitively inhibits human LPA receptors LPAR1, LPAR3, and LPAR2 with reported IC 50 values of 0.34, 0.93, and 6.5 μM, respectively (David et al, ). As a control, we confirmed that Ki16425 does not alter calcium transients evoked by potassium (data not shown).…”

New insights into the autotaxin/LPA axis in cancer development and metastasis

“…In addition, assessing drug efficacy in the clinic is a general high-reaching achievement, but that may become much more challenging in the context of LPA biology because complex pathways involve several distinct G protein-coupled receptors, inflammatory cytokine pathways, and transactivation of receptor tyrosine kinase signaling through metalloproteinase activations that drive ATX/LPA receptor axis in cancer. Therefore, efforts should be made on defining specific biomarkers linked to specific LPA receptor activities that would ensure both clinical validation of anti-LPA treatments and follow up disease progression/remission of patients receiving directed therapies [68]. 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 47...…”