BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival.
BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival.
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DOI：
10.1158/1078-0432.ccr-11-0735
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发表时间：
2011-10-01
期刊：
影响因子：
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通讯作者：
Lancaster JM
中科院分区：
文献类型：
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作者：
Marchion DC;Cottrill HM;Xiong Y;Chen N;Bicaku E;Fulp WJ;Bansal N;Chon HS;Stickles XB;Kamath SG;Hakam A;Li L;Su D;Moreno C;Judson PL;Berchuck A;Wenham RM;Apte SM;Gonzalez-Bosquet J;Bloom GC;Eschrich SA;Sebti S;Chen DT;Lancaster JM
尽管最初对化疗敏感，但卵巢癌（OVCA）通常会产生耐药性，这限制了患者的生存。使用来自289名患者和一组癌细胞系的标本和/或基因组数据，我们探索了OVCA化疗耐药性演变的全基因组表达变化，并将细胞死亡（BAD）凋亡途径的BCL 2拮抗剂表征为化疗敏感性和患者生存的决定因素。连续OVCA细胞顺铂处理与全基因组表达变化的测量平行进行。对与顺铂耐药性增加（EC 50）相关的基因进行了通路分析。在患者样品和细胞系中评估了BAD途径表达和BAD蛋白磷酸化作为化学敏感性和/或临床结果的决定因素以及作为治疗靶点。体外诱导的OVCA顺铂耐药与BAD通路的表达相关（P < 0.001）。在OVCA细胞系和原代标本中，BAD蛋白磷酸化与铂类耐药相关（n = 147，P < 0.0001），也与患者总生存率相关（n = 134，P = 0.0007）。靶向调节BAD磷酸化水平影响顺铂敏感性。47基因BAD通路评分与体外磷酸化BAD水平和142例晚期（III/IV）浆液性OVCA患者的生存率相关。通过对数秩检验，BAD磷酸化或BAD通路评分与OVCA手术细胞减灭状态的整合与总生存率显著相关（分别为P = 0.004和<0.0001）。BAD凋亡途径影响OVCA化疗敏感性和总生存期，可能通过调节BAD磷酸化。该途径作为治疗反应、患者存活的生物标志物和作为有前景的治疗靶点具有临床相关性。
Despite initial sensitivity to chemotherapy, ovarian cancers (OVCA) often develop drug-resistance, which limits patient survival. Using specimens and/or genomic data from 289 patients and a panel of cancer cell lines, we explored genome-wide expression changes that underlie the evolution of OVCA chemo-resistance and characterized the BCL2 antagonist of cell death (BAD) apoptosis pathway as a determinant of chemo-sensitivity and patient survival. Serial OVCA cell cisplatin treatments were performed in parallel with measurements of genome-wide expression changes. Pathway analysis was performed on genes associated with increasing cisplatin-resistance (EC50). BAD-pathway expression and BAD-protein phosphorylation were evaluated in patient samples and cell lines as determinants of chemo-sensitivity and/or clinical outcome and as therapeutic targets. Induced in vitro OVCA cisplatin-resistance was associated with BAD-pathway expression (P < 0.001). In OVCA cell lines and primary specimens, BAD-protein phosphorylation was associated with platinum-resistance (n = 147, P < 0.0001) and also with overall patient survival (n = 134, P = 0.0007). Targeted modulation of BAD-phosphorylation levels influenced cisplatin sensitivity. A 47-gene BAD-pathway score was associated with in vitro phosphorylated-BAD levels and with survival in 142 patients with advanced-stage (III/IV) serous OVCA. Integration of BAD-phosphorylation or BAD-pathway score with OVCA surgical cytoreductive status was significantly associated with overall survival by log-rank test (P = 0.004 and <0.0001, respectively). The BAD apoptosis pathway influences OVCA chemo-sensitivity and overall survival, likely via modulation of BAD-phosphorylation. The pathway has clinical relevance as a biomarker of therapeutic response, patient survival, and as a promising therapeutic target.