Withaferin-A suppress AKT induced tumor growth in colorectal cancer cells.
Withaferin-A suppress AKT induced tumor growth in colorectal cancer cells.
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DOI：
10.18632/oncotarget.7351
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发表时间：
2016-03-22
期刊：
影响因子：
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通讯作者：
Damodaran C
中科院分区：
文献类型：
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作者：
Suman S;Das TP;Sirimulla S;Alatassi H;Ankem MK;Damodaran C
AKT基因的致癌激活已成为结直肠癌（CRC）侵袭性的关键决定因素;因此，研究集中在靶向AKT信号传导以治疗晚期CRC。在这项研究中，我们探讨了在临床前（体外和体内）模型中，醉茄素A（WA）对过表达AKT的CRC细胞的抗肿瘤作用。我们的研究结果表明，WA，一种天然化合物，导致显着抑制AKT活性，并导致抑制细胞增殖，迁移和侵袭，通过下调上皮间质转化（EMT）标志物在CRC细胞过度表达AKT。在异种移植模型中，WA的口服给药显著抑制了AKT诱导的侵袭性肿瘤生长。分子生物学分析表明，AKT及其下游促生存信号分子的表达降低可能是肿瘤抑制的原因。此外，一些重要的EMT标志物，即，在WA处理的过表达AKT的人CRC细胞中观察到Snail、Slug、β-连环蛋白和波形蛋白。在WA治疗的肿瘤中，微血管形成和血管长度的显著抑制是明显的，这与血管生成标记物RETIC的低表达相关。总之，本研究强调了AKT激活在诱导CRC细胞中的细胞增殖、血管生成和EMT中的关键作用，并表明WA可以克服AKT诱导的CRC细胞增殖和肿瘤生长。
The oncogenic activation of AKT gene has emerged as a key determinant of the aggressiveness of colorectal cancer (CRC); hence, research has focused on targeting AKT signaling for the treatment of advanced stages of CRC. In this study, we explored the anti-tumorigenic effects of withaferin A (WA) on CRC cells overexpressing AKT in preclinical (in vitro and in vivo) models. Our results indicated that WA, a natural compound, resulted in significant inhibition of AKT activity and led to the inhibition of cell proliferation, migration and invasion by downregulating the epithelial to mesenchymal transition (EMT) markers in CRC cells overexpressing AKT. The oral administration of WA significantly suppressed AKT-induced aggressive tumor growth in a xenograft model. Molecular analysis revealed that the decreased expression of AKT and its downstream pro-survival signaling molecules may be responsible for tumor inhibition. Further, significant inhibition of some important EMT markers, i.e., Snail, Slug, β-catenin and vimentin, was observed in WA-treated human CRC cells overexpressing AKT. Significant inhibition of micro-vessel formation and the length of vessels were evident in WA-treated tumors, which correlated with a low expression of the angiogenic marker RETIC. In conclusion, the present study emphasizes the crucial role of AKT activation in inducing cell proliferation, angiogenesis and EMT in CRC cells and suggests that WA may overcome AKT-induced cell proliferation and tumor growth in CRC.