CAT3, a novel agent for medulloblastoma and glioblastoma treatment, inhibits tumor growth by disrupting the Hedgehog signaling pathway. Issue 2 (28th October 2016)

• Record Type: Journal Article
• Authors: Chen, Ju; Lv, Haining; Hu, Jinping; Ji, Ming; Xue, Nina; Li, Chao; Ma, Shuanggang; Zhou, Qin; Lin, Bin; Li, Yan; Yu, Shishan; Chen, Xiaoguang
• Is Part Of: Cancer letters. Volume 381:Issue 2(2016)
• Page Start: 391
• Page End: 403
• Publication Date: 2016-10-28
• Subjects: Medulloblastoma -- Glioblastoma -- Hedgehog -- Smo -- Gli1; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.07.030
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: In this study, CAT3, as the prodrug of PF403, was designed and synthesized and metabolized into PF403 in vivo, and displayed significant antitumor activity against MB and GBM in vitro and in vivo. Mechanistic study revealed that the antitumor effects of CAT3 were primarily mediated by interrupting Hedgehog (Hh) pathway. PF403, the active form of CAT3, inhibited the cell surface accumulation of Smoothened (Smo) receptor by directly binding and enhancing the interaction of Smo with the repressor Ptch1. Furthermore, PF403 significantly repressed Gli1 nuclear accumulation and transcription by increasing the Sufu-Gli1 and PKA-Gli1 interactions. Collectively, our studies for the first time support the hypothesis that CAT3 is a promising therapeutic agent for the treatment of Hh-driven MB and GBM. Abstract: Medulloblastoma (MB) and glioblastoma (GBM) are the most prevalent malignant brain tumors. The identification of novel therapeutic strategies is urgent for MB and GBM patients. Herein, we discovered 13a-( S )-3-Hydroxyl-6, 7-dimethoxyphenanthro[9, 10- b ]-indolizidine (PF403) strongly exhibited inhibitory activity against Hedgehog (Hh) pathway-hyperactivated MB and GBM cells with a 50% inhibitory concentration (IC50 ) of 0.01 nM. CAT3 was designed and synthesized as the prodrug of PF403 and displayed significant in vivo efficacy against MB and GBM. Mechanistic study revealed that CAT3 inhibited MB and GBM primarily by interrupting the Hh signaling pathway. At the molecular level, PF403 inhibited the cell surface accumulation of the Smoothened (Smo) receptor by directly binding or enhancing the interaction of Smo with the repressor Ptch1. Furthermore, PF403 significantly repressed Gli1 nuclear accumulation and transcription by promoting Sufu-Gli1 and PKA-Gli1 interactions. Collectively, our studies support the hypothesis that CAT3 is a promising therapeutic agent for the treatment of Hh-driven MB and GBM.