Data for: Anticarin-β shows a promising anti-osteosarcoma effect by specifically inhibiting CCT4 to impair proteostasis

Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex (TRiC) contains eight paralogous subunits (CCT1-8), and assists the folding of as many as 10 % of cytosolic proteome. TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma, and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma. Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis.

与健康的、未经转化的细胞不同，癌细胞在产生参与肿瘤发展的蛋白质时，其蛋白质稳态网络承受着巨大的压力。癌细胞对分子伴侣的依赖性更高，以维持蛋白质稳态。伴侣蛋白T复合蛋白环状复合物（TRiC）包含八个同源亚基（CCT1-8），并协助折叠高达10%的细胞质蛋白质组。TRiC对于某些癌症的进展至关重要，但TRiC亚基在骨肉瘤中的作用尚待研究。本研究中，我们发现CCT4/TRiC与人类骨肉瘤显著相关，并在骨肉瘤细胞的存活中发挥着至关重要的作用。我们鉴定出一种名为anticarin-β的化合物，能够特异性地结合并抑制CCT4。相比于正常细胞，anticarin-β在癌细胞中表现出更高的选择性。机制上，anticarin-β有效地阻断了CCT4介导的STAT3成熟。anticarin-β在骨肉瘤的原位和患者来源的异种移植模型中显示出显著的抗肿瘤活性。综上所述，我们的数据揭示了CCT4在骨肉瘤中的关键作用，并提出了通过破坏CCT4和蛋白质稳态来治疗骨肉瘤的潜在治疗策略。