Chulalongkorn University, Bangkok, 10330, Thailand.
Apoptosis. 2010 May;15(5):574-85. doi: 10.1007/s10495-010-0461-4.
Anoikis, an apoptosis triggered by loss of cell anchorage, has been shown to be a principal mechanism of inhibition of tumor metastasis. Recently, anti-apoptotic Bcl-2 and Cav-1 proteins have been demonstrated to be highly associated with tumor metastasis and apoptosis resistance. Curcumin, a major active component of turmeric, Curcuma longa, has been shown to inhibit neoplastic evolution and tumor progression; however, the underlying mechanisms are unclear. In this study, we investigated the effect of curcumin on cell anoikis as a possible mechanism of anti-tumorigenic action of curcumin, and evaluated the potential role of Bcl-2 and Cav-1 in this process. Our results showed that ectopic expression of either Bcl-2 or Cav-1 induced anoikis resistance of lung carcinoma H460 cells. Curcumin downregulated Bcl-2 protein during anoikis and sensitized the cells to detachment-induced apoptosis, whereas it had no significant effect on Cav-1 protein expression. Bcl-2 down-regulation as well as anoikis enhancement by curcumin were inhibited by superoxide anion scavenger, Mn(III)tetrakis(4-benzoic acid) porphyrin chloride, but were unaffected by other ROS scavengers including catalase and deferoxamine, suggesting that superoxide anion is a key player in the downregulation of Bcl-2 by curcumin. Furthermore, we provided evidence that curcumin decreased Bcl-2 level through ubiquitin-proteasomal degradation which sensitized cells to detachment-induced apoptosis. These findings indicate a novel pathway for curcumin regulation of Bcl-2 and provide a key mechanism of anoikis regulation that may be exploited for metastatic cancer treatment.
失巢凋亡是细胞失去锚着时所触发的凋亡，它已被证明是抑制肿瘤转移的主要机制。最近，抗凋亡 Bcl-2 和 Cav-1 蛋白已被证明与肿瘤转移和凋亡抵抗高度相关。姜黄素是姜黄 Curcuma longa 的主要活性成分，已被证明能抑制肿瘤的演进和肿瘤的进展；然而，其潜在的机制尚不清楚。在这项研究中，我们研究了姜黄素对细胞失巢凋亡的影响，作为姜黄素抗肿瘤作用的一种可能机制，并评估了 Bcl-2 和 Cav-1 在这一过程中的潜在作用。我们的结果表明，Bcl-2 或 Cav-1 的异位表达诱导肺癌 H460 细胞失巢凋亡抵抗。姜黄素在失巢凋亡过程中下调 Bcl-2 蛋白，使细胞对脱落诱导的凋亡敏感，而对 Cav-1 蛋白表达没有显著影响。超氧阴离子清除剂 Mn(III)四(4-苯甲酸)卟啉氯化物抑制了姜黄素对 Bcl-2 的下调和对失巢凋亡的增强，但对其他 ROS 清除剂如过氧化氢酶和去铁胺没有影响，这表明超氧阴离子是姜黄素下调 Bcl-2 的关键因素。此外，我们提供了证据表明，姜黄素通过泛素-蛋白酶体降解降低 Bcl-2 水平，使细胞对脱落诱导的凋亡敏感。这些发现表明了姜黄素调节 Bcl-2 的一种新途径，并为失巢凋亡调节提供了一个关键机制，可能被用于转移性癌症的治疗。
