Resistance to ursolic acid-induced apoptosis through involvement of melanogenesis and COX-2/PGE2 pathways in human M4Beu melanoma cancer cells.
Melanoma is one of the most aggressive forms of cancer with a continuously growing incidence worldwide and is usually resistant to chemotherapy agents, which is due in part to a strong resistance to apoptosis. Previously, we had showed that B16-F0 murine melanoma cells undergoing apoptosis are able to delay their own death induced by ursolic acid (UA), a natural pentacyclic triterpenoid compound. We had demonstrated that tyrosinase and TRP-1 up-regulation in apoptotic cells and the subsequent production of melanin were implicated in an apoptosis resistance mechanism. Several resistance mechanisms to apoptosis have been characterized in melanoma such as hyperactivation of DNA repair mechanisms, drug efflux systems, and reinforcement of survival signals (PI3K/Akt, NF-κB and Raf/MAPK pathways). Otherwise, other mechanisms of apoptosis resistance involving different proteins, such as cyclooxygenase-2 (COX-2), have been described in many cancer types. By using a strategy of specific inhibition of each ways, we suggested that there was an interaction between melanogenesis and COX-2/PGE2 pathway. This was characterized by analyzing the COX-2 expression and activity, the expression of tyrosinase and melanin production. Furthermore, we showed that anti-proliferative and proapoptotic effects of UA were mediated through modulation of multiple signaling pathways including Akt and ERK-1/2 proteins. Our study not only uncovers underlying molecular mechanisms of UA action in human melanoma cancer cells but also suggest its great potential as an adjuvant in treatment and cancer prevention.
Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France.
Lama
L
Hassan
Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France.
Aline
A
Pinon
Laboratoire National de Référence (LNR), Université Mohammed VI des Sciences de la Santé, Casablanca, Morocco.
Youness
Y
Limami
Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France.
Josiane
J
Seeman
Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France.
Chloe
C
Fidanzi-Dugas
Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France.
Frederique
F
Martin
Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences, Lebanese University, Beirut, Lebanon.
Bassam
B
Badran
Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France.
Alain
A
Simon
Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France. Electronic address: bertrand.liagre@unilim.fr.
Bertrand
B
Liagre
D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008543:Melanins / Q000096:biosynthesis*; D008545:Melanoma / Q000201:enzymology / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D000097245:Ursolic Acid
D001241:Aspirin; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D008543:Melanins; D051057:Proto-Oncogene Proteins c-akt; D014315:Triterpenes; D000097245:Ursolic Acid
Apoptosis; COX-2; Melanogenesis; Melanoma cancer cells; Survival pathways; Ursolic acid