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

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.

• Authors: Li Sun, Yuan Huang, Yeying Liu, Yujie Zhao, Xiaoxiao He, Lingling Zhang, Feng Wang, Yingjie Zhang
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 9 Pg. 911 (09 05 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 30185800 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• BBC3 protein, human
• FOXO3 protein, human
• Forkhead Box Protein O3
• NF-kappa B
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, metabolism)
• Female
• Forkhead Box Protein O3 (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• HCT116 Cells
• HT29 Cells
• Humans
• Mice
• Mice, Nude
• NF-kappa B (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Transcription, Genetic (drug effects)