title: Enhanced apoptotic effects by downregulating Mcl-1: evidence for the improvement of photodynamic therapy with Celecoxib.
abstract: Tumor cells exposed to sub-lethal photodynamic therapy (PDT) cause cellular rescue responses that lead to resistance to the therapy, including expression of angiogenic factors and survival molecules. However, the mechanisms contributing to the resistance are yet to be fully understood. Here, we show for the first time that Mcl-1, an anti-apoptotic protein, plays an important role in protecting cells from PDT-induced apoptosis. In contrast to the reduction in the anti-apoptotic proteins Bcl-2 and Bcl-xl, sub-lethal PDT induces an increase in Mcl-1 expression. Silencing Mcl-1 sensitizes tumor cells to PDT-induced apoptosis, and ectopic expression of Mcl-1 significantly delays Bax translocation to mitochondria and inhibits caspase-3 activity following PDT. Mcl-1 expression is associated closely with activated AKT signaling following PDT. AKT can regulate Mcl-1 expression through GSK-3β and NF-κB at the protein and transcriptional levels, respectively. Inhibition of AKT by Wortmannin or siRNA significantly reduces the levels of Mcl-1 mRNA and protein and enhances PDT-induced apoptosis. Treatment with Celecoxib, a non-steroidal anti-inflammatory drug (NSAID), is shown to downregulate Mcl-1 expression, and enhances PDT-induced apoptosis both in vitro and in vivo. This down-regulation is closely related to the inhibition effect of Celecoxib on the AKT/GSK-3β pathway, and was blocked upon addition of GSK-3β inhibitor LiCl or the proteasome inhibitor MG132. These results suggest that Mcl-1 is a potential target for improving the antitumor efficiency of PDT. A loss in Mcl-1 by inhibiting AKT promotes PDT-induced apoptosis through the mitochondrial pathway. This also provides a novel rationale for utilizing Celecoxib to improve the efficacy of PDT.
authors.affiliation: MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou 510631, China.
authors.forename: Jiaxing
authors.initials: J
authors.lastname: Song
authors.forename: Qun
authors.initials: Q
authors.lastname: Chen
authors.forename: Da
authors.initials: D
authors.lastname: Xing
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D000068579:Celecoxib; D002470:Cell Survival; D017323:Dihematoporphyrin Ether / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D010778:Photochemotherapy / Q000379:methods*; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D000077191:Wortmannin; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; C494826:BAX protein, human; D007976:Leupeptins; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; D017323:Dihematoporphyrin Ether; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D000068579:Celecoxib; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000077191:Wortmannin