Abstract 3326: Targeting lysophosphatidic acid receptor 1 (LPAR1) radiosensitizes poor prognosis cancers
Authors: Khudanyan Arpine , Dadey David , Karvas Rowan , Kotipatruni Rama , Hallahan Dennis , Thotala Dinesh 
Published: August 2015

Therapies for poor prognosis cancers, such as lung cancer and glioblastoma, are limited due to radio-resistance and tumor recurrence. Development of molecular targeted therapy can serve as a potential method to improve the efficacy of radiation therapy in both glioblastoma and lung cancer. Ionizing radiation (IR) can activate a series of pro-survival pathways which contributes to the pathogenesis of cancer cells. Among these pathways, cytosolic phospholipase A2 (cPLA2) is an integral component which is activated by IR. Following activation, cPLA2 cleaves arachidonic acid to form phosphatidylcholine (PC) and yields lysophosphatidylcholine (LPC). Autotaxin (ATX) then converts LPC to lysophosphatidic acid (LPA). LPA acts through G-protein-coupled receptors (GPCR) such as LPA1, LPA2, and LPA3, influencing various fundamental cellular functions. Specifically, these receptors can modulate the ability of cancer cells to proliferate, differentiate, and survive. Earlier we have shown that inhibition of ATX decreases invasion and enhances radiation sensitivity of cancer cells. In the present study we investigated the role of LPA receptors and its effect on radioresistance in human A549, murine Lewis Lung Carcinoma (LLC), and rat C6 glioma cells.

We analyzed the expression levels of the three LPA receptors in various cancer cell lines including lung, brain, breast and pancreatic cancer cells. We found high expression of LPA1 in LLC, C6 and A549, which we thus chose for further study. Using inhibitors of LPA1/LPA3, Ki16425 and VPC 12249, we determined the effect of LPA1 inhibition on the AKT and ERK activation. Inhibition of LPA1 attenuated phosphorylation of both AKT and ERK in irradiated lung cancer cells. This implicated LPA1 in the regulation of pro-survival signaling, and we hypothesized that LPA1 regulation could influence radioresistance in lung cancer and glioma cells. We targeted LPA1 using siRNA in LLC, C6 and A549 cells which led to an average of 50% reduction in clonogenic survival and cell proliferation after irradiation. Similar results were obtained when LLC and A549 cells were treated with 10μM Ki16425 or 10μM VPC 12249. In addition, LLC and A549 cells which were treated with combinations of radiation and LPA1 inhibitors and analyzed using cell invasion assays showed a 70% reduction in cancer cell invasion. These results indicate that LPA1 could serve as a novel target for cancer treatment due to its ability to enhance the efficacy of radiotherapy in multiple cancer cell lines.

Citation Format: Arpine Khudanyan, David Dadey, Rowan Karvas, Rama Kotipatruni, Dennis Hallahan, Dinesh Thotala. Targeting lysophosphatidic acid receptor 1 (LPAR1) radiosensitizes poor prognosis cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3326. doi:10.1158/1538-7445.AM2015-3326