A role of Rab7 in stabilizing EGFR‐Her2 and in sustaining Akt survival signal
A role of Rab7 in stabilizing EGFR‐Her2 and in sustaining Akt survival signal
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DOI：
10.1002/jcp.23023
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发表时间：
2012-06
影响因子：
5.6
通讯作者：
Tuanlao Wang;Ming Zhang;Zexu Ma;Ke Guo;V. Tergaonkar;Q. Zeng;W. Hong
中科院分区：
文献类型：
--
作者：
Tuanlao Wang;Ming Zhang;Zexu Ma;Ke Guo;V. Tergaonkar;Q. Zeng;W. Hong
Rab7在调节内吞运输中起重要作用。鉴于膜交通在信号传导和疾病中的新作用，我们研究了Rab7在肿瘤发生中的可能作用。通过shRNA介导的敲低Rab7在A431和MCF7癌细胞中的作用进行了研究。令我们惊讶的是，Rab7敲低有效地抑制了癌细胞在软琼脂中的非锚定生长。Anoikis（基质脱落触发的细胞凋亡）增强，而磷酸化（活性）Akt（关键存活因子）水平显著降低。同样有趣的是，当Rab7被敲除时，EGFR和Her2水平显著降低。当用HSP90抑制剂格尔达霉素（GA）处理敲除的细胞时，观察到EGFR和Her2水平的更强的降低。低浓度GA （50-100 nm）诱导Rab7敲除的细胞凋亡，而非对照细胞，这表明Rab7和HSP90共同促进了EGFR和Her2的最佳稳定性，并保护癌细胞免于凋亡。Rab7似乎可以保护EGFR和Her2免受蛋白体介导的降解。这些结果表明Rab7可能参与保护EGFR和Her2不被蛋白体降解，并维持最佳的Akt存活信号（特别是在细胞脱离或HSP90被抑制时）。Rab7是Hsp90抑制剂联合治疗的潜在新靶点。j .细胞。中国生物医学工程学报，2016,31(2):388 - 397。©2011 Wiley期刊公司
Rab7 plays an important role in regulating endocytic traffic. In view of an emerging role of membrane traffic in signaling and diseases, we have examined the possible role of Rab7 in oncogenesis. The role of Rab7 was investigated using shRNA‐mediated knockdown in A431 and MCF7 cancer cells. To our surprise, Rab7 knockdown effectively suppressed anchorage‐independent growth of cancer cells in soft agar. Anoikis (matrix‐detachment triggered apoptosis) was enhanced, while the level of phosphorylated (active) Akt (which is a key survival factor) was significantly reduced. Also intriguing was the observation that EGFR and Her2 levels were significantly reduced when Rab7 was knocked‐down. More robust reduction of EGFR and Her2 levels was observed when knocked‐down cells were treated with HSP90 inhibitor geldanamycin (GA). Low concentration of GA (50–100 nm)‐induced apoptosis of the Rab7 knocked‐down cells but not control cells, suggesting that Rab7 and HSP90 together contribute to the optimal stability of EGFR and Her2 as well as to protect cancer cells from apoptosis. Rab7 seems to protect EGFR and Her2 from proteosome‐mediated degradation. These results suggest that Rab7 is likely involved in protecting EGFR and Her2 from being degraded by the proteosome and in maintaining optimal Akt survival signal (especially during cell detachment or when HSP90 is inhibited). Rab7 is potentially a novel target for combinatory therapy with Hsp90 inhibitors. J. Cell. Physiol. 227: 2788–2797, 2012. © 2011 Wiley Periodicals, Inc.