Smith Vicki, Hobbs Stephen, Court William, Eccles Suzanne, Workman Paul, Kelland Lloyd R
CRC Center for Cancer Therapeutics, The Institute of Cancer Research, Sutton, UK.
Anticancer Res. 2002 Jul-Aug;22(4):1993-9.
ErbB2 is overexpressed in 25-30% of breast and ovarian cancers, correlates with poor prognosis and lower survival and has also been associated with chemoresistance. We have established an isogenic pair of human ovarian cells that differ only in the expression of erbB2 protein in order to elucidate the role of the protein in determining cellular sensitivity to various drugs and agents. These included cisplatin and paclitaxel, the main drugs used in the treatment of ovarian cancer, and also various signal transduction inhibitors affecting the ras and P13K pathways. Transfection of erbB2 resulted in cells stably overexpressing the protein and showing increased motility compared to the empty vector control cells. In cells overexpressing erbB2, the most notable effect on chemosensitivity was that of significantly increased (5-fold) sensitivity to the heat shock protein 90 (HSP90) molecular chaperone inhibitor geldanamycin. In contrast, erbB2-overexpressing cells showed statistically significant resistance to cisplatin, the P13K inhibitor LY294002 and the tyrosine kinase inhibitor emodin. No significant difference in growth inhibition was observed after exposure to paclitaxel, two additional HSP90 inhibitors radicicol and 17AAG, the cyclin-dependent kinase inhibitor flavopiridol, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor PD153035, the mek inhibitor U0126 or the famesyl transferase inhibitor R115777. Exposure of cells to geldanamycin, 17AAG, emodin, LY294002 and cisplatin led to depletion of erbB2 in the transfected cells. These data suggest that erbB2 status in ovarian cancr may contribute to chemosensitivity, in some cases leading to increased sensitivity (as with geldanamycin) but in other cases leading to resistance (as with cisplatin).
在25% - 30%的乳腺癌和卵巢癌中，ErbB2呈过表达，与预后不良和较低生存率相关，还与化疗耐药有关。我们建立了一对同基因的人卵巢细胞，它们仅在ErbB2蛋白表达上存在差异，以阐明该蛋白在决定细胞对各种药物和试剂敏感性方面的作用。这些药物包括顺铂和紫杉醇，它们是治疗卵巢癌的主要药物，还有各种影响ras和PI3K途径的信号转导抑制剂。转染ErbB2导致细胞稳定过表达该蛋白，与空载体对照细胞相比，其运动性增强。在过表达ErbB2的细胞中，对化学敏感性最显著的影响是对热休克蛋白90（HSP90）分子伴侣抑制剂格尔德霉素的敏感性显著增加（5倍）。相反，过表达ErbB2的细胞对顺铂、PI3K抑制剂LY294002和酪氨酸激酶抑制剂大黄素表现出统计学上显著的耐药性。暴露于紫杉醇、另外两种HSP90抑制剂放线菌酮和17AAG、细胞周期蛋白依赖性激酶抑制剂黄酮哌啶醇、表皮生长因子受体（EGFR）酪氨酸激酶抑制剂PD153035、mek抑制剂U0126或法尼基转移酶抑制剂R115777后，未观察到生长抑制的显著差异。将细胞暴露于格尔德霉素、17AAG、大黄素、LY294002和顺铂会导致转染细胞中ErbB2的耗竭。这些数据表明，卵巢癌中的ErbB2状态可能有助于化学敏感性，在某些情况下导致敏感性增加（如与格尔德霉素相关），但在其他情况下导致耐药性（如与顺铂相关）。
