Inhibitor SBFI26 suppresses the malignant progression of castration-resistant PC3-M cells by competitively binding to oncogenic FABP5

• Published in: Oncotarget Vol. 8; no. 19; pp. 31041 - 31056
• Main Authors: Al-Jameel, Waseem, Gou, Xiaojun, Forootan, Shiva S, Al Fayi, Majed Saad, Rudland, Philip S, Forootan, Farzad S, Zhang, Jiacheng, Cornford, Philip A, Hussain, Syed A, Ke, Youqiang
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 09-05-2017
• Subjects: Animals; Antineoplastic Agents - pharmacology; Binding, Competitive; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Cyclobutanes - pharmacology; Dicarboxylic Acids - pharmacology; Disease Models, Animal; Disease Progression; Drug Discovery; Drug Screening Assays, Antitumor; Fatty Acid-Binding Proteins - antagonists & inhibitors; Fatty Acid-Binding Proteins - metabolism; Fatty Acids - metabolism; Humans; Ligands; Male; Mice; Neoplasm Metastasis; PPAR gamma - agonists; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Protein Binding; Research Paper; Xenograft Model Antitumor Assays; SBFI26; FABP5; metastasis; CRPC; PPARγ
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.16055

Castration resistant-prostate cancer is largely impervious to feather hormonal therapy and hence the outlook for patients is grim. Here we use an approach to attach the recently discovered Achilles heel. The experimental treatment established in this study is based on the recent discovery that it is the FABP5-PPARγ-VEGF signalling axis, rather than the androgen receptor pathway, played a dominant role in promoting the malignant progression of castration resistant prostate cancer cells. Treatments have been established in mice by suppressing the biological activity of FABP5 using a chemical inhibitor SBFI26. The inhibitor significantly suppressed the proliferation, migration, invasiveness and colony formation of PC3-M cells in vitro. It also produced a highly significant suppression of both the metastases and the primary tumours developed from cancer cells implanted orthotopically into the prostate glands of the mice. The inhibitor SBFI26 interferes with the FABP5-PPARγ- signalling pathway at the initial stage of the signal transduction by binding competitively to FABP5 to inhibit cellular fatty acid uptake. This avoids the fatty-acid stimulation of PPARγ and prevents it activating the down-stream regulated cancer-promoting genes. This entirely novel experimental approach to treating castration- resistant prostate cancer is completely different from current treatments that are based on androgen-blockade therapy.