FABP5-Related Signalling Pathway Used as Therapeutic Target for Castration-Resistance Prostate Cancer

• Main Author: Al-Jameel, Waseem Hanna
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2017
• Subjects: Bioinformatics; Cellular biology; Genetics; Oncology; Public health
• ISBN: 9798684631672

Castration resistant-prostate cancer is largely impervious to feather hormonal therapy and hence the outlook for patients is grim. Increased FABP5 expression plays a crucial role in promoting castration-resistant prostate cancer. 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 and a novel bio-inhibitor, dmrFABP5. Both inhibitors significantly suppressed the proliferation, migration, invasiveness and colony formation of castration-resistant prostate cancer PC3-M cells in vitro. They also produced a highly significant suppression of both metastatic rates and average sizes of primary tumours developed from cancer cells implanted orthotopically into the prostate gland of the mice. Strikingly, the bio-inhibitor dmrFABP5, a mutated FABP5 incapable of binding to fatty acids, produced a much better suppression of both primary tumour growth and metastasis. Both inhibitors interfere with the FABP5-PPARγ- signalling pathway, but by different mechanisms. 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. In contrast, dmrFABP5 can block the fatty-acid stimulation of PPARγ and prevent it activating the down-stream regulated cancer-promoting genes. This is an entirely novel experimental approach and completely different from current treatments that are based on androgen-blockade therapy.