Grünwald Viktor, DeGraffenried Linda, Russel Douglas, Friedrichs William E, Ray Ratna B, Hidalgo Manuel
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
Cancer Res. 2002 Nov 1;62(21):6141-5.
Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) is a lipid phosphatase with putative tumor suppressing abilities, which is frequently mutated in prostate cancer. Loss of PTEN leads to constitutive activation of the phosphatidylinositol 3'-kinase/serine-threonine kinase (Akt) signal transduction pathway and has been associated with resistance to chemotherapy. This study aimed to determine the effects of PTEN status and treatment with rapamycin, an inhibitor of mTOR, in the response of prostate cancer cell lines to doxorubicin. The DU-145 PTEN-positive cell line was significantly more susceptible to the antiproliferative effects of doxorubicin as compared with the PTEN-negative PC-3 cell line. Transfection of PTEN into the PC3 cells decreased the activation of Akt and the downstream mTOR-regulated 70-kDa S6 (p70(s6k)) kinase and reversed the resistance to doxorubicin in these cells, indicating that changes in PTEN status/Akt activation modulate the cellular response to doxorubicin. Treatment of PC-3 PTEN-negative cells with rapamycin inhibited 70-kDa S6 kinase and increased the proliferative response of these cells to doxorubicin, so that it was comparable with the responses of PTEN-positive DU-145 cells and the PC-3-transfected cells. Furthermore, treatment of mice bearing the PTEN-negative PC-3 prostate cancer xenografts with CCI-779, an ester of rapamycin in clinical development combined with doxorubicin, inhibited the growth of the doxorubicin-resistant PC-3 tumors confirming the observations in vitro. Thus, rapamycin and CCI-779, by interacting with downstream intermediates in the phosphatidylinositol 3'-kinase/Akt signaling pathway, reverse the resistance to doxorubicin conferred by PTEN mutation/Akt activation. These results provide the rationale to explore in clinical trials whether these agents increase the response to chemotherapy of patients with PTEN-negative/Akt active cancers.
10号染色体缺失的磷酸酶及张力蛋白同源物（PTEN）是一种具有假定肿瘤抑制能力的脂质磷酸酶，在前列腺癌中经常发生突变。PTEN的缺失导致磷脂酰肌醇3'-激酶/丝氨酸-苏氨酸激酶（Akt）信号转导通路的组成性激活，并与化疗耐药相关。本研究旨在确定PTEN状态以及用雷帕霉素（一种mTOR抑制剂）治疗对前列腺癌细胞系对阿霉素反应的影响。与PTEN阴性的PC-3细胞系相比，DU-145 PTEN阳性细胞系对阿霉素的抗增殖作用明显更敏感。将PTEN转染到PC3细胞中可降低Akt的激活以及下游mTOR调节的70-kDa S6（p70(s6k)）激酶的激活，并逆转这些细胞对阿霉素的耐药性，表明PTEN状态/Akt激活的变化可调节细胞对阿霉素的反应。用雷帕霉素处理PTEN阴性的PC-3细胞可抑制70-kDa S6激酶，并增加这些细胞对阿霉素的增殖反应，使其与PTEN阳性的DU-145细胞和转染了PTEN的PC-3细胞的反应相当。此外，用临床开发中的雷帕霉素酯CCI-779联合阿霉素治疗携带PTEN阴性PC-3前列腺癌异种移植物的小鼠，可抑制阿霉素耐药的PC-3肿瘤的生长，证实了体外观察结果。因此，雷帕霉素和CCI-779通过与磷脂酰肌醇3'-激酶/Akt信号通路中的下游中间体相互作用，逆转了PTEN突变/Akt激活所赋予的对阿霉素的耐药性。这些结果为在临床试验中探索这些药物是否能增加PTEN阴性/Akt激活的癌症患者对化疗的反应提供了理论依据。
