Georgia Health Sciences University Cancer Center, Augusta, Georgia 30912.
Georgia Health Sciences University Cancer Center, Augusta, Georgia 30912.
J Biol Chem. 2012 Mar 23;287(13):10051-10059. doi: 10.1074/jbc.M111.335000. Epub 2012 Feb 7.
Inactivation of HSP90 and HSP70 leads to loss of invasion in a variety of cancer cell types, presumably as a result of destabilization of, as yet, undefined clients of these molecular chaperones that influence this phenotype. The WASF3 gene has been shown to be up-regulated in high-grade tumors and its down-regulation leads to loss of invasion and metastasis. WASF3 phosphorylation by ABL kinase is essential for its ability to regulate invasion. Mass spectroscopy analysis now shows that HSP90 is present in the WASF3 immunocomplex from prostate cancer cells. Inactivation of HSP90 in these and other cell types does not affect WASF3 stability but prevents its phosphoactivation as a result of destabilization of ABL. HSP70 was also found in the WASF3 immunocomplex and inactivation of HSP70 results in destabilization of WASF3 through proteasome degradation. Knockdown of WASF3, HSP90, and HSP70 individually, all lead to loss of invasion but as knockdown of WASF3 in the presence of robust expression of HSP90/70 has the same effect, it seems that the influence these chaperone proteins have on invasion is mediated, at least in part, by their control over the critical invasion promoting capacity of the WASF3 protein. Overexpression of HSP70 in WASF3 null cells does not enhance invasion. These observations suggest that targeting HSP90/70 may have efficacy in reducing cancer cell invasion.
HSP90 和 HSP70 的失活会导致多种癌细胞类型的侵袭能力丧失，这可能是由于这些分子伴侣的尚未明确的客户不稳定，从而影响了这种表型。已经表明，WASF3 基因在高级别肿瘤中上调，其下调会导致侵袭和转移能力丧失。ABL 激酶对 WASF3 的磷酸化对于其调节侵袭的能力至关重要。质谱分析现在表明，HSP90 存在于前列腺癌细胞中的 WASF3 免疫复合物中。在这些和其他细胞类型中，HSP90 的失活不会影响 WASF3 的稳定性，但会由于 ABL 的不稳定而阻止其磷酸化激活。WASF3 免疫复合物中也发现了 HSP70，HSP70 的失活会导致 WASF3 通过蛋白酶体降解而不稳定。单独敲低 WASF3、HSP90 和 HSP70 都会导致侵袭能力丧失，但由于在 HSP90/70 表达稳健的情况下敲低 WASF3 会产生相同的效果，因此这些伴侣蛋白对侵袭的影响似乎至少部分是通过它们对 WASF3 蛋白的关键侵袭促进能力的控制来介导的。在 WASF3 缺失细胞中过表达 HSP70 不会增强侵袭能力。这些观察结果表明，靶向 HSP90/70 可能在降低癌细胞侵袭能力方面具有疗效。
