Mcl-1 Interacts with Akt to Promote Lung Cancer Progression

• Type of Material: Article
• Authors: Guo Chen, Emory University; Dongkyoo Park, Emory University; Andrew T. Magis, Institute for Systems Biology; Madhusmita Behera, Emory University; Suresh Ramalingam, Emory University; Taofeek Owonikoko, Emory University; Gabriel Sica, Emory University; Keqiang Ye, Emory University; Chao Zhang, Emory University; Zhengjia Chen, Emory University; Walter Curran Jr, Emory University; Xingming Deng, Emory University
• Language: English
• Date: 2019-12-15
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/0008-5472.CAN-19-0950
• Title of Journal or Parent Work: Cancer Research
• Volume: 79
• Issue: 24
• Start Page: 6126
• End Page: 6138
• Grant/Funding Information: This work was supported by NCI, National Institutes of Health grants R01CA193828, R01CA136534, R01CA200905 and P50CA217691(to X. Deng), by the Winship Research Informatics, Pathology and Integrated Cellular Imaging shared resource,; The cores supported by the Winship Cancer Institute of Emory University (P30CAJ38292); By the Winship Fashion a Cure Research Scholar Award (to X. Deng), a philanthropic award provided by the Winship Cancer Institute of Emory University, and by Winship Endowment Fund (to X. Deng).
• Keywords: Oncology; Mechanisms; DNA-damage; Life Sciences & Biomedicine; Activation; Expression; Kinase; K-RAS; Localizes; PTEN; Science & Technology
• Research Categories: Biology, Genetics; Health Sciences, Oncology; Chemistry, Biochemistry; Health Sciences, Pathology

Abstract

Mcl-1 is a unique antiapoptotic Bcl2 family protein that functions as a gatekeeper in manipulating apoptosis and survival in cancer cells. Akt is an oncogenic kinase that regulates multiple cellular functions and its activity is significantly elevated in human cancers. Here we discovered a cross-talk between Mcl-1 and Akt in promoting lung cancer cell growth. Depletion of endogenous Mcl-1 from human lung cancer cells using CRISPR/Cas9 or Mcl-1 shRNA significantly decreased Akt activity, leading to suppression of lung cancer cell growth in vitro and in xenografts. Mechanistically, Mcl-1 directly interacted via its PEST domain with Akt at the pleckstrin homology (PH) domain. It is known that the interactions between the PH domain and kinase domain (KD) are important for maintaining Akt in an inactive state. The binding of Mcl-1/PH domain disrupted intramolecular PH/KD interactions to activate Akt. Intriguingly, Mcl-1 expression correlated with Akt activity in tumor tissues from patients with non–small cell lung cancer. Using the Mcl-1–binding PH domain of Akt as a docking site, we identified a novel small molecule, PH-687, that directly targets the PH domain and disrupts Mcl-1/Akt binding, leading to suppression of Akt activity and growth inhibition of lung cancer in vitro and in vivo. By targeting the Mcl-1/Akt interaction, this mechanism-driven agent provides a highly attractive strategy for the treatment of lung cancer. Significance: These findings indicate that targeting Mcl-1/ Akt interaction by employing small molecules such as PH-687 represents a potentially new and effective strategy for cancer treatment.