title: The P2Y2/Src/p38/COX-2 pathway is involved in the resistance to ursolic acid-induced apoptosis in colorectal and prostate cancer cells.
abstract: One of the hallmarks of cancer is resistance to apoptosis. Elucidating the mechanisms of how cancer cells evade or delay apoptosis should lead to novel therapeutic strategies. Previously, we showed that HT-29 colorectal cancer cells undergoing apoptosis overexpressed cyclooxygenase-2 (COX-2), in a p38 dependent pathway, to delay ursolic acid-induced apoptosis. Here, we focused on elucidating the upstream signaling pathways regulating this resistance mechanism. The role of ATP as an extracellular signaling molecule took a long time to be accepted. In recent years, ATP and its analogs, via the activation of specific purinergic receptors, have been implicated in many biological processes including cell proliferation, differentiation and apoptosis. In the present report, we have demonstrated a novel role involving purinergic receptors and particularly the P2Y(2) receptor in resistance to ursolic acid-induced apoptosis in both colorectal HT-29 and prostate DU145 cancer cells. We found that ursolic acid induced an increase in intracellular ATP and P2Y(2) transcript levels. Upon activation, P2Y(2) activated Src which in turn phosphorylated p38 leading to COX-2 overexpression which induced resistance to apoptosis in both HT-29 and DU145 cells. Furthermore, Ca(2+)-independent PLA(2) (iPLA(2)) and Ca(2+)-dependent secretory PLA(2) (sPLA(2)) were responsible for arachidonic acid release, the substrate of COX-2. Our findings document that apoptosis triggering was dependent on protein kinase C (PKC) activation in both cell lines after ursolic acid treatment.
authors.affiliation: Université de Limoges, Laboratoire de Chimie des Substances Naturelles, EA 1069, Faculté de Pharmacie, 2 rue du Docteur Marcland, FR 3503 GEIST, 87025 Limoges Cedex, France.
authors.forename: Youness
authors.initials: Y
authors.lastname: Limami
authors.forename: Aline
authors.initials: A
authors.lastname: Pinon
authors.forename: David Yannick
authors.initials: DY
authors.lastname: Leger
authors.forename: Emilie
authors.initials: E
authors.lastname: Pinault
authors.forename: Christiane
authors.initials: C
authors.lastname: Delage
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Beneytout
authors.forename: Alain
authors.initials: A
authors.lastname: Simon
authors.forename: Bertrand
authors.initials: B
authors.lastname: Liagre
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D016718:Arachidonic Acid / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D054501:Group II Phospholipases A2 / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D058473:Receptors, Purinergic P2Y2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014315:Triterpenes / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism; D000097245:Ursolic Acid
chemical_list: D000255:Adenosine Triphosphate; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; D054501:Group II Phospholipases A2; D058473:Receptors, Purinergic P2Y2; D014315:Triterpenes; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases; D000097245:Ursolic Acid; C496540:PTGS2 protein, human; C516293:PLA2G2D protein, human