title: Chemotherapeutic sensitization by endoplasmic reticulum stress: increasing the efficacy of taxane against prostate cancer.
abstract: Taxanes are first line drugs for treating prostate cancer recurrence after the failure of anti-androgen therapy. There is a need to make taxanes more effective since they only provide palliative benefit. Exploiting endoplasmic reticulum (ER) stress death signaling to enhance drug efficacy has not been delineated. Human PC-3 cells were used as a model of hormone refractory prostate cancer. Thapsigargin and methylseleninic acid (MSA) were examined as sensitizers. Thapsigargin is a classic ER stress inducer. The activity of MSA in inducing ER stress has recently been studied by our group. The efficacy of single drug and the various combinations was evaluated by measuring apoptosis with a cell death ELISA kit. Thapsigargin increased the cell killing potency of paclitaxel or docetaxel by 10- to 12-fold, while MSA caused a 5- to 8-fold increase. Since thapsigargin is not used clinically because of its toxicity, the follow-up experiments were done with MSA. To test the hypothesis that a threshold level of ER stress is crucial to chemotherapeutic sensitization, three different approaches designed to dampen the severity of ER stress induced by MSA were examined. Lowering ER stress consistently attenuated the efficacy of MSA/taxane. GADD153 is a pro-apoptotic transcription factor which is upregulated during ER stress. Knocking down GADD153 by siRNA also reduced the cell killing effect of MSA/taxane. Both the intrinsic and extrinsic apoptotic pathways were involved in the sensitization mechanism. Our study supports the idea that marshalling ER stress apoptotic response is conducive to chemotherapeutic sensitization.
authors.affiliation: Department of Cancer Prevention & Control, Roswell Park Cancer Institute, Buffalo, New York 14263 , USA. WuYu@RoswellPark.org
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.forename: Melissa
authors.initials: M
authors.lastname: Fabritius
authors.forename: Clement
authors.initials: C
authors.lastname: Ip
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D004797:Enzyme-Linked Immunosorbent Assay; D005562:Formazans / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000378:metabolism; D016566:Organoselenium Compounds / Q000008:administration & dosage; D017239:Paclitaxel / Q000008:administration & dosage; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013778:Tetrazolium Salts / Q000378:metabolism; D019284:Thapsigargin / Q000008:administration & dosage; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D014162:Transfection
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D005562:Formazans; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D016566:Organoselenium Compounds; D034741:RNA, Small Interfering; D043823:Taxoids; D013778:Tetrazolium Salts; D051742:Transcription Factor CHOP; D000077143:Docetaxel; C079782:MTT formazan; D019284:Thapsigargin; C008493:methylselenic acid; D017239:Paclitaxel