1. Stomatin-Mediated Inhibition of the Akt Signaling Axis Suppresses Tumor Growth
- Author
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Khurelbaatar Tsevelnorov, Akio Shimizu, Akinori Wada, Akihiro Kawauchi, Akira Sato, Mohammad Khusni B Ahmat Amin, Joanne Ern Chi Soh, Masahiro Komeno, Hisakazu Ogita, Le Kim Chi Nguyen, Rasel Molla, and Nor Idayu A. Rahman more...
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Stromal cell ,Cell ,Apoptosis ,Cell Communication ,Mice, SCID ,Transfection ,3-Phosphoinositide-Dependent Protein Kinases ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Mice, Inbred NOD ,medicine ,Animals ,Humans ,Protein kinase B ,Aged ,Cell Proliferation ,Tumor microenvironment ,biology ,Chemistry ,Membrane Proteins ,Prostatic Neoplasms ,Cancer ,Hep G2 Cells ,medicine.disease ,Xenograft Model Antitumor Assays ,Hsp90 ,Tumor Burden ,HEK293 Cells ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Cancer research ,Stromal Cells ,Stomatin ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
The growth and progression of cancers are crucially regulated by the tumor microenvironment where tumor cells and stromal cells are mutually associated. In this study, we found that stomatin expression was markedly upregulated by the interaction between prostate cancer cells and stromal cells. Stomatin suppressed cancer cell proliferation and enhanced apoptosis in vitro and inhibited xenograft tumor growth in vivo. Stomatin inhibited Akt activation, which is mediated by phosphoinositide-dependent protein kinase 1 (PDPK1). PDPK1 protein stability was maintained by its binding to HSP90. Stomatin interacted with PDPK1 and interfered with the PDPK1–HSP90 complex formation, resulting in decreased PDPK1 expression. Knockdown of stomatin in cancer cells elevated Akt activation and promoted cell increase by promoting the interaction between PDPK1 and HSP90. Clinically, stomatin expression levels were significantly decreased in human prostate cancer samples with high Gleason scores, and lower expression of stomatin was associated with higher recurrence of prostate cancer after the operation. Collectively, these findings demonstrate the tumor-suppressive effect of stromal-induced stomatin on cancer cells. Significance: These findings reveal that interactions with stromal cells induce expression of stomatin in prostate cancer cells, which suppresses tumor growth via attenuation of the Akt signaling axis. more...
- Published
- 2021