Saito Y, Swanson X, Mhashilkar A M, Oida Y, Schrock R, Branch C D, Chada S, Zumstein L, Ramesh R
Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Gene Ther. 2003 Nov;10(23):1961-9. doi: 10.1038/sj.gt.3302100.
The tumor-suppressor gene PTEN encodes a multifunctional phosphatase that is mutated in a variety of human cancers. PTEN inhibits the phosphatidylinositol 3-kinase pathway and downstream functions, including activation of Akt/protein kinase B (PKB), cell survival, and cell proliferation in tumor cells carrying mutant- or deletion-type PTEN. In such tumor cells, enforced expression of PTEN decreases cell proliferation through cell-cycle arrest at G1 phase accompanied, in some cases, by induction of apoptosis. More recently, the tumor-suppressive effect of PTEN has been reported in ovarian and thyroid tumors that are wild type for PTEN. In the present study, we examined the tumor-suppressive effect of PTEN in human colorectal cancer cells that are wild type for PTEN. Adenoviral-mediated transfer of PTEN (Ad-PTEN) suppressed cell growth and induced apoptosis significantly in colorectal cancer cells (DLD-1, HT29, and SW480) carrying wtPTEN than in normal colon fibroblast cells (CCD-18Co) carrying wtPTEN. This suppression was induced through downregulation of the Akt/PKB pathway, dephosphorylation of focal adhesion kinase (FAK) and mitogen-activated protein kinase (MAPK) and cell-cycle arrest at the G2/M phase, but not the G1 phase. Furthermore, treatment of human colorectal tumor xenografts (HT-29, and SW480) with Ad-PTEN resulted in significant (P=0.01) suppression of tumor growth. These results indicate that Ad-PTEN exerts its tumor-suppressive effect on colorectal cancer cells through inhibition of cell-cycle progression and induction of cell death. Thus Ad-PTEN may be a potential therapeutic for treatment of colorectal cancers.
肿瘤抑制基因PTEN编码一种多功能磷酸酶，该酶在多种人类癌症中发生突变。PTEN抑制磷脂酰肌醇3激酶途径及其下游功能，包括Akt/蛋白激酶B（PKB）的激活、细胞存活以及携带突变型或缺失型PTEN的肿瘤细胞中的细胞增殖。在这类肿瘤细胞中，PTEN的强制表达通过使细胞周期停滞在G1期来降低细胞增殖，某些情况下还伴有细胞凋亡的诱导。最近，在PTEN野生型的卵巢和甲状腺肿瘤中也报道了PTEN的肿瘤抑制作用。在本研究中，我们检测了PTEN在PTEN野生型的人结肠癌细胞中的肿瘤抑制作用。腺病毒介导的PTEN（Ad-PTEN）转移在携带野生型PTEN的结肠癌细胞（DLD-1、HT29和SW480）中比在携带野生型PTEN的正常结肠成纤维细胞（CCD-18Co）中更显著地抑制细胞生长并诱导细胞凋亡。这种抑制是通过下调Akt/PKB途径、使粘着斑激酶（FAK）和丝裂原活化蛋白激酶（MAPK）去磷酸化以及使细胞周期停滞在G2/M期而非G1期来实现的。此外，用Ad-PTEN处理人结肠肿瘤异种移植瘤（HT-29和SW480）导致肿瘤生长显著（P=0.0）抑制。这些结果表明，Ad-PTEN通过抑制细胞周期进程和诱导细胞死亡对结肠癌细胞发挥其肿瘤抑制作用。因此，Ad-PTEN可能是治疗结肠癌的一种潜在疗法。
