2. Academic Validation
  3. Ipatasertib, a novel Akt inhibitor, induces transcription factor FoxO3a and NF-κB directly regulates PUMA-dependent apoptosis

Ipatasertib, a novel Akt inhibitor, induces transcription factor FoxO3a and NF-κB directly regulates PUMA-dependent apoptosis

  • Cell Death Dis. 2018 Sep 5;9(9):911. doi: 10.1038/s41419-018-0943-9.
Li Sun 1 2,  Yuan Huang 1,  Yeying Liu 1,  Yujie Zhao 1,  Xiaoxiao He 1,  Lingling Zhang 3,  Feng Wang 4 5,  Yingjie Zhang 6 7
Affiliations

Affiliations

  • 1 College of Biology, Hunan University, Changsha, 410082, China.
  • 2 Department of Out-patient, Affiliated Hospital of Hebei University of Engineering, Handan, 056002, China.
  • 3 Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha, 410013, China. zhll0807@csu.edu.cn.
  • 4 Department of Gastroenterology, The Tenth People's Hospital of Shanghai, Tongji University, Shanghai, 200072, China. wolffeng2000@hotmail.com.
  • 5 Shenzhen Institute, Hunan University, Shenzhen, China. wolffeng2000@hotmail.com.
  • 6 College of Biology, Hunan University, Changsha, 410082, China. yingjiezhang@hnu.edu.cn.
  • 7 Shenzhen Institute, Hunan University, Shenzhen, China. yingjiezhang@hnu.edu.cn.
PMID: 30185800 DOI: 10.1038/s41419-018-0943-9
Abstract

Colon Cancer is one of the three common malignant tumors, with a lower survival rate. Ipatasertib, a novel highly selective ATP-competitive pan-Akt inhibitor, shows a strong antitumor effect in a variety of carcinoma, including colon Cancer. However, there is a lack of knowledge about the precise underlying mechanism of clinical therapy for colon Cancer. We conducted this study to determine that ipatasertib prevented colon Cancer growth through PUMA-dependent Apoptosis. Ipatasertib led to p53-independent PUMA activation by inhibiting Akt, thereby activating both FoxO3a and NF-κB synchronously that will directly bind to PUMA promoter, up-regulating PUMA transcription and Bax-mediated intrinsic mitochondrial Apoptosis. Remarkably, Akt/FoxO3a/PUMA is the major pathway while Akt/NF-κB/PUMA is the secondary pathway of PUMA activation induced by ipatasertib in colon Cancer. Knocking out PUMA eliminated ipatasertib-induced Apoptosis both in vitro and in vivo (xenografts). Furthermore, PUMA is also indispensable in combinational therapies of ipatasertib with some conventional or novel drugs. Collectively, our study demonstrated that PUMA induction by FoxO3a and NF-κB is a critical step to suppress the growth of colon Cancer under the therapy with ipatasertib, which provides some theoretical basis for clinical assessment.

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