School of Biomedical Sciences and Pharmacy, The University of Newcastle, New South Wales, Australia.
School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia.
Mol Carcinog. 2018 Feb;57(2):284-294. doi: 10.1002/mc.22755. Epub 2017 Nov 14.
Past studies have shown that mutant KRAS colon cancer cells are susceptible to apoptosis induced by the HSP90 inhibitor AUY922. Nevertheless, intrinsic and acquired resistance remains an obstacle for the potential application of the inhibitor in the treatment of the disease. Here we report that Mcl-1 is important for survival of colon cancer cells in the presence of AUY922. Mcl-1 was upregulated in mutant KRAS colon cancer cells selected for resistance to AUY922-induced apoptosis. This was due to its increased stability mediated by Bcl-2-associated athanogene domain 3 (BAG3), which was also increased in resistant colon cancer cells by heat shock factor 1 (HSF1) as a result of chronic endoplasmic reticulum (ER) stress. Functional investigations demonstrated that inhibition of Mcl-1, BAG3, or HSF1 triggered apoptosis in resistant colon cancer cells, and rendered AUY922-naïve colon cancer cells more sensitive to the inhibitor. Together, these results identify that the HSF1-BAG3-Mcl-1 signal axis is critical for protection of mutant KRAS colon cancer cells from AUY922-induced apoptosis, with potential implications for targeting HSF1/BAG3/Mcl-1 to improve the efficacy of AUY922 in the treatment of colon cancer.
过去的研究表明，突变型 KRAS 结肠癌细胞容易被 HSP90 抑制剂 AUY922 诱导凋亡。然而，内在和获得性耐药仍然是该抑制剂在疾病治疗中应用的障碍。在这里，我们报告 Mcl-1 对于 AUY922 存在时结肠癌细胞的存活很重要。在对 AUY922 诱导的凋亡具有耐药性的突变型 KRAS 结肠癌细胞中，Mcl-1 上调。这是由于其稳定性增加，这是由 Bcl-2 相关的 Athanogene 结构域 3（BAG3）介导的，BAG3 在耐药性结肠癌细胞中也由于慢性内质网（ER）应激而由热休克因子 1（HSF1）增加。功能研究表明，抑制 Mcl-1、BAG3 或 HSF1 可在耐药性结肠癌细胞中引发凋亡，并使 AUY922 敏感的结肠癌细胞对抑制剂更敏感。总之，这些结果表明 HSF1-BAG3-Mcl-1 信号轴对于保护突变型 KRAS 结肠癌细胞免受 AUY922 诱导的凋亡至关重要，这可能暗示靶向 HSF1/BAG3/Mcl-1 以提高 AUY922 治疗结肠癌的疗效。
