Mcl-1 Interacts with Akt to Promote Lung Cancer Progression.

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.

• Authors: Guo Chen, Dongkyoo Park, Andrew T Magis, Madhusmita Behera, Suresh S Ramalingam, Taofeek K Owonikoko, Gabriel L Sica, Keqiang Ye, Chao Zhang, Zhengjia Chen, Walter J Curran, Xingming Deng
• Journal: Cancer research (Cancer Res) Vol. 79 Issue 24 Pg. 6126-6138 (12 15 2019) ISSN: 1538-7445 [Electronic] United States
• PMID: 31662324 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• CRISPR-Cas Systems (genetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy, mortality, pathology)
• Cell Line, Tumor
• Disease Progression
• Follow-Up Studies
• Gene Knockout Techniques
• Humans
• Kaplan-Meier Estimate
• Lung (pathology)
• Lung Neoplasms (drug therapy, mortality, pathology)
• Male
• Mice
• Molecular Docking Simulation
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Prognosis
• Protein Binding (drug effects)
• Protein Domains (drug effects)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Tissue Array Analysis
• Xenograft Model Antitumor Assays