Progesterone induces apoptosis in TRAIL-resistant ovarian cancer cells by circumventing c-FLIPL overexpression.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) holds great potential as an anticancer drug, since it induces selective cell death in cancer cells but not in normal ones. However, cancer cells often acquire resistance to TRAIL, which hinders its clinical efficacy. We previously demonstrated that progesterone triggers apoptosis in human ovarian cancer (OCa) cells. In the present study, we evaluated the prospect of utilizing progestins in combination with TRAIL to enhance cell death in TRAIL-sensitive (OVCA 420, OVCA 429, and OVCA 433) and -resistant (OVCA 432) OCa cell lines. TRAIL sensitivity (60-80% cell kill) bore no correlation with expression of the TRAIL receptors (DR4, DR5) or their decoys (DcR1 and DcR2), but was associated with activation of caspase-8 and -3, and downregulation of the long isoform of FLICE-like inhibitory protein (c-FLIP(L)), an anti-apoptosis mediator. Small interfering RNA-mediated knockdown of c-FLIP(L) expression restored TRAIL sensitivity in OVCA 432 cells. Induction of c-FLIP(L) overexpression increased TRAIL resistance in TRAIL-sensitive lines. Thus, persistent high level of c-FLIP(L) expression likely mediates TRAIL resistance in OCa cells. Treatment of OCa cells with progesterone enhanced TRAIL-induced cell death (>85%), but only in TRAIL-sensitive cell lines. Combined treatment with two progestins was superior to single progestin treatment, with progesterone plus medroxyprogesterone acetate (MPA) achieving over 85% cell kill in both TRAIL-sensitive and -resistant OCa cell lines. Significantly, unlike TRAIL, progestin-induced cell death did not involve c-FLIP(L) downregulation. Hence, combined progestin regimens, with or without TRAIL, may serve as an effective therapy for OCa by circumventing the anti-apoptotic action of c-FLIP(L).
Syed
Viqar
V
Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Mukherjee
Kasturi
K
Godoy-Tundidor
Sonia
S
Ho
Shuk-Mei
SM
D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D009640:Norethindrone / Q000031:analogs & derivatives / Q000494:pharmacology; D000077563:Norethindrone Acetate; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D011374:Progesterone / Q000494:pharmacology*; D011372:Progestins / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000494:pharmacology*; D053319:Tumor Necrosis Factor Decoy Receptors / Q000378:metabolism
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D058851:GPI-Linked Proteins; D011372:Progestins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; C108661:TNFRSF10C protein, human; C451501:TNFRSF10D protein, human; C505653:TNFSF10 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D011374:Progesterone; D000077563:Norethindrone Acetate; D017258:Medroxyprogesterone Acetate; D020169:Caspases; D009640:Norethindrone