膀胱癌是全球十种最常见的癌症之一，由于对膀胱癌恶性发展分子机制的认知限制，其预后在过去三十年间并未显著改善。因此，迫切需要发现新的治疗药物或分子靶点，以改善膀胱癌患者的预后。最近有报道称，SC66是一种新型AKT的异构性抑制剂，对各种癌细胞具有强烈的抗癌作用。然而，SC66在膀胱癌中的抗癌作用机制仍然大部分未知。因此，本研究旨在进行一系列的分子和细胞生物学实验，以验证SC66在体外对膀胱癌的抗癌作用和潜在机制，并建立异种移植瘤模型以证实其在体内的抗癌作用。我们的结果显示，SC66以剂量依赖的方式抑制了膀胱癌细胞的增殖，诱导了线粒体介导的凋亡，并启动了自噬。此外，我们的结果表明，SC66引发的凋亡和自噬是内质网应激依赖的。有趣的是，自噬的激活在内质网应激引起的SC66处理中部分保护了膀胱癌细胞免受凋亡的影响。本研究显示，SC66通过抑制细胞增殖并诱导凋亡来发挥其对膀胱癌的抗癌作用。同时还揭示了抑制自噬可以增加SC66在膀胱癌中的细胞毒性作用。总的来说，这是首个关于SC66通过内质网应激途径介导的抗癌作用的研究，并首次报道了SC66在膀胱癌中无需AKT的抗癌机制。最后，探索SC66引起的凋亡、自噬和内质网应激之间的关系表明，SC66是膀胱癌患者的一种有前景的新型治疗药物。版权所有 © 2023. 由Elsevier B.V.出版。

Bladder cancer is among the ten most prevalent cancer types worldwide, and its prognosis has not improved significantly in the past three decades because of cognitive limitations in the molecular mechanisms that drive the malignant progression of bladder cancer. Therefore, there is an urgent need to identify new therapeutic drugs or molecular targets to improve the prognosis of patients with bladder cancer. SC66, a novel allosteric inhibitor of AKT, has recently been reported to exert potent anticancer effects on various cancer cells. However, the mechanisms underlying its anticancer effects in bladder cancer remain largely unknown. Consequently, this study aimed to conduct a series of molecular and cellular biology experiments to verify the anticancer effect and potential mechanism of action of SC66 in bladder cancer in vitro. A xenograft tumor model was established to confirm its anticancer role in vivo. Our results showed that SC66 inhibited cell proliferation, triggered mitochondria-mediated apoptosis, and initiated autophagy in bladder cancer cells dose-dependently. In addition, our results suggested that SC66-caused apoptosis and autophagy were endoplasmic reticulum stress-dependent. Interestingly, the activation of autophagy can partially protect bladder cancer cells from apoptosis under endoplasmic reticulum stress induced by SC66 treatment. This study shows that SC66 exerts its anticancer impact on bladder cancer by inhibiting cell proliferation and inducing apoptosis. It also reveals that inhibiting autophagy can increase the cytotoxic effects of SC66 in bladder cancer. Overall, this is the first study on the anticancer effect of SC66 mediated by the endoplasmic reticulum stress pathway and the first report on the AKT-independent anticancer mechanism of SC66 in bladder cancer. Conclusively, exploring the relationship between apoptosis, autophagy, and endoplasmic reticulum stress induced by SC66 indicates that SC66 is a promising novel agent for patients with bladder cancer.Copyright © 2023. Published by Elsevier B.V.