Platelet‐activating factor‐receptor dependent pathway mediates gemcitabine chemotherapy‐induced microvesicle particles release in pancreatic cancer cells

Abstract

Studies including ours have shown that pro‐oxidative stressors such as chemotherapeutic agents generate oxidized lipids with platelet‐activating factor (PAF) agonistic activity. These PAF‐agonists bind with and activate the widely‐expressed G‐protein coupled, PAF‐receptor (PAF‐R), implicated in various pathophysiological diseases including cancer. Notably, recent reports from our group have demonstrated that these PAF‐agonists are transported extracellularly via microvesicle particles (MVP). While the role of PAF‐R in mediating chemotherapy effects has been documented, its significance in chemotherapy‐induced MVP release in pancreatic cancer model has not been studied. To that end, the current studies determined the functional significance of PAF‐R in clinically relevant gemcitabine chemotherapy‐induced MVP release in human pancreatic cancer cells. Our studies using PAF‐R‐expressing (PANC‐1), and deficient (Hs766T) cells demonstrate that gemcitabine induces MVP release in a PAF‐R‐dependent manner. Blocking of PAF‐R via PAF‐R antagonist or inhibition of MVP biogenesis via acid sphingomyelinase (aSMase) enzyme inhibitor, significantly attenuated gemcitabine‐induced MVP release from PANC‐1 cells, however, exerted no effects in Hs766T cells. Importantly, lipid extracts from MVP, isolated from gemcitabine‐treated PANC‐1 cells, contained appreciable amounts of PAF‐agonists. This was measured by a well‐defined and specific approach of accessing PAF‐agonists generation via interleukin‐8 (IL‐8) secretion from PAF‐R‐expressing human epidermoid KBP cells, and not from PAF‐R‐deficient KBM cells. These results indicate that gemcitabine‐generated PAF‐agonists are transported extracellularly via MVP. Mechanistically, pretreatment with extracellular signal‐regulated kinase (ERK1/2) or p38 inhibitors, significantly abrogated gemcitabine‐induced MVP release. These findings indicate the involvement of mitogen‐activated protein kinase (MAPK) pathway in PAF‐R‐dependent gemcitabine‐induced MVP release. In sum, these studies provide the significance of PAF‐R in gemcitabine‐induced MVP release as well as the rationale of evaluating PAF‐R targeting agents with gemcitabine or gemcitabine‐based chemotherapy approaches against pancreatic cancer.Support or Funding InformationThe financial support from the NIH K22 [ES023850] and Elsa U. Pardee Foundation [670645] grants are greatly acknowledged.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.