Stassi Giorgio, Garofalo Michela, Zerilli Monica, Ricci-Vitiani Lucia, Zanca Ciro, Todaro Matilde, Aragona Federico, Limite Gennaro, Petrella Giuseppe, Condorelli Gerolama
Department of Cellular and Molecular Biology, Federico II University of Naples, Naples.
Cancer Res. 2005 Aug 1;65(15):6668-75. doi: 10.1158/0008-5472.CAN-04-4009.
Killing of tumor cells by cytotoxic therapies, such as chemotherapy or gamma-irradiation, is predominantly mediated by the activation of apoptotic pathways. Refractoriness to anticancer therapy is often due to a failure in the apoptotic pathway. The mechanisms that control the balance between survival and cell death in cancer cells are still largely unknown. Tumor cells have been shown to evade death signals through an increase in the expression of antiapoptotic molecules or loss of proapoptotic factors. We aimed to study the involvement of PED, a molecule with a broad antiapoptotic action, in human breast cancer cell resistance to chemotherapeutic drugs-induced cell death. We show that human breast cancer cells express high levels of PED and that AKT activity regulates PED protein levels. Interestingly, exogenous expression of a dominant-negative AKT cDNA or of PED antisense in human breast cancer cells induced a significant down-regulation of PED and sensitized cells to chemotherapy-induced cell death. Thus, AKT-dependent increase of PED expression levels represents a key molecular mechanism for chemoresistance in breast cancer.
细胞毒性疗法（如化疗或伽马射线照射）对肿瘤细胞的杀伤作用主要是通过激活凋亡途径介导的。抗癌治疗的难治性通常是由于凋亡途径的失效。癌细胞中控制生存与细胞死亡平衡的机制仍大多未知。肿瘤细胞已被证明可通过增加抗凋亡分子的表达或丧失促凋亡因子来逃避死亡信号。我们旨在研究具有广泛抗凋亡作用的分子PED在人乳腺癌细胞对化疗药物诱导的细胞死亡的抗性中的作用。我们发现人乳腺癌细胞表达高水平的PED，且AKT活性调节PED蛋白水平。有趣的是，在人乳腺癌细胞中外源表达显性负性AKT cDNA或PED反义核酸可导致PED显著下调，并使细胞对化疗诱导的细胞死亡敏感。因此，AKT依赖的PED表达水平增加代表了乳腺癌化疗耐药的关键分子机制。
