Re-expression of TSLC1 in a non-small-cell lung cancer cell line induces apoptosis and inhibits tumor growth
Re-expression of TSLC1 in a non-small-cell lung cancer cell line induces apoptosis and inhibits tumor growth
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DOI：
10.1038/sj.onc.1207756
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发表时间：
2004-07-22
期刊：
影响因子：
8
通讯作者：
Ghosh, HP
中科院分区：
文献类型：
--
作者：
Mao, XL;Seidlitz, E;Ghosh, HP
TSLC 1肿瘤抑制基因在许多人类癌症组织和细胞系中沉默，包括肺癌、前列腺癌、肝癌、胃癌、胰腺癌和乳腺癌。TSLC 1在非小细胞肺癌（NSCLC）细胞系A549中的表达抑制裸鼠的致瘤性。然而，TSLC 1作用的分子机制尚未阐明。在本研究中，我们表明，从重组腺病毒载体（Ad-TSLC 1）的表达TSLC 1抑制细胞增殖和诱导凋亡的非小细胞肺癌细胞系A549。我们还证明，通过瘤内注射Ad-TSLC 1，A549细胞诱导的裸鼠皮下肿瘤生长被抑制到70-80%的程度。TSLC 1的再表达也导致凋亡蛋白酶caspase-3的活化，伴随着其底物聚（ADP-核糖）聚合酶（PARP）的裂解。TSLC 1的抗增殖和促凋亡活性需要位于细胞质结构域中的FERM结合和PDZ相互作用基序的存在。我们的研究结果表明，TSLC 1蛋白的促凋亡和肿瘤抑制活性，并建议TSLC 1的基因治疗的潜力。
The TSLC1 tumor-suppressor gene is silenced in a number of human cancer tissues and cell lines, including lung, prostate, liver, stomach, pancreatic, and breast cancers. Expression of TSLC1 in a non-small-cell lung cancer (NSCLC) cell line A549 suppresses tumorigenicity in nude mice. However, the molecular mechanism of TSLC1 action is not yet elucidated. In the present study, we show that the expression of TSLC1 from a recombinant adenovirus vector (Ad-TSLC1) inhibited cell proliferation and induced apoptosis in the NSCLC cell line A549. We also demonstrated that subcutaneous tumor growth in nude mice induced by A549 cells was suppressed to the extent of 70-80% by intratumoral injection of Ad-TSLC1. Re-expression of TSLC1 also resulted in activation of the apoptotic protease caspase-3, accompanied by the cleavage of its substrate poly (ADP-ribose) polymerase (PARP). The antiproliferative and proapoptotic activity of TSLC1 required the presence of the FERM-binding and PDZ-interacting motifs located in the cytoplasmic domain. Our results demonstrate the proapoptotic and oncosuppressive activity of TSLC1 protein, and suggest the potential of TSLC1 for gene therapy.