Patients with advanced-stage cervical cancer have a high rate of morbidity and mortality, predominantly due to the metastasis of cervical cancer cells. Therefore, the development of novel agents to prevent metastasis is required for improved cervical cancer therapeutics. SNX-2112, a potent and selective Hsp90 inhibitor, is an anticancer candidate in clinical trials for the treatment of some solid tumors and lymphomas. However, the effects of SNX-2112 on the migration and invasion of cervical cancer cells are unclear. This study aimed at exploring the effects of SNX-2112 on the migration and invasion of cervical cancer cells and revealing the underlying molecular mechanisms. We found that SNX-2112 significantly decreased the viability, colony formation ability, and migration of HeLa and U14 cells. The invasiveness of HeLa cells and the proteins involved in metastasis were markedly reduced after SNX-2112 treatment. SNX-2112 inactivated the focal adhesion kinase (FAK) and inhibited the expression levels of matrix metallopeptidase (MMP)-9, MMP-2, SLUG, SNAIL, β-catenin, and Vimentin. Furthermore, SNX-2112 inhibited the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway in HeLa cells by decreasing the phosphorylation of Akt, mTOR, S6, and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). It also reduced the expression levels of the endoplasmic reticulum (ER)-localized molecular chaperones, Calnexin and BiP, and unfolded protein response (UPR)-related proteins IRE1α and PERK, suggesting that SNX-2112 can suppress ER stress and thus, inactivate the UPR in HeLa cells. Taken together, these findings indicate that SNX-2112 may efficiently suppress the proliferation, migration, and invasion of cervical cancer cells by inhibiting the Akt/mTOR pathway and could serve as a candidate drug for the treatment of human cervical cancer.

中文翻译：

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Hsp90抑制剂SNX-2112通过抑制Akt / mTOR信号通路来抑制子宫颈癌细胞的增殖，迁移和侵袭

晚期宫颈癌患者的发病率和死亡率较高，这主要归因于宫颈癌细胞的转移。因此，需要开发预防转移的新型药物来改善宫颈癌的治疗方法。SNX-2112是一种有效且选择性的Hsp90抑制剂，在临床试验中可用于某些实体瘤和淋巴瘤的抗癌候选药物。但是，SNX-2112对子宫颈癌细胞迁移和侵袭的影响尚不清楚。这项研究旨在探讨SNX-2112对子宫颈癌细胞迁移和侵袭的影响，并揭示其潜在的分子机制。我们发现SNX-2112显着降低了HeLa和U14细胞的活力，集落形成能力以及迁移。SNX-2112处理后，HeLa细胞和转移蛋白的侵袭力明显降低。SNX-2112使粘着斑激酶（FAK）失活，并抑制基质金属肽酶（MMP）-9，MMP-2，SLUG，SNAIL，β-catenin和Vimentin的表达水平。此外，SNX-2112通过降低Akt，mTOR，S6和真核翻译起始因子4E结合蛋白1（4EBP1）的磷酸化，抑制HeLa细胞中的蛋白激酶B（Akt）/哺乳动物雷帕霉素（mTOR）信号转导通路靶标。它还降低了内质网（ER）本地化分子伴侣，钙结合蛋白和BiP的表达水平，以及未折叠的蛋白反应（UPR）相关蛋白IRE1α和PERK的表达水平，这表明SNX-2112可以抑制ER应激，从而使内质网失活。 HeLa细胞中的UPR。在一起