Dataset Information

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

ABSTRACT: 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-PPAR?-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-PPAR?- 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 PPAR? 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.

SUBMITTER: Al-Jameel W

PROVIDER: S-EPMC5458187 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Al-Jameel Waseem W Gou Xiaojun X Forootan Shiva S SS Al Fayi Majed Saad MS Rudland Philip S PS Forootan Farzad S FS Zhang Jiacheng J Cornford Philip A PA Hussain Syed A SA Ke Youqiang Y

Oncotarget 20170501 19

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. Treatment ...[more]

PMID: 28415688

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Project description:Fatty acid‑binding protein 5 (FABP5) and androgen receptor (AR) are critical promoters of prostate cancer. In the present study, the effects of knocking out the FABP5 or AR genes on malignant characteristics of prostate cancer cells were investigated, and changes in the expression of certain key proteins in the FABP5 (or AR)‑peroxisome proliferator activated receptor‑γ (PPARγ)‑vascular endothelial growth factor (VEGF) signaling pathway were monitored. The results obtained showed that FABP5‑ or AR‑knockout (KO) led to a marked suppression of the malignant characteristics of the cells, in part, through disrupting this signaling pathway. Moreover, FABP5 and AR are able to interact with each other to regulate this pathway, with FABP5 controlling the dominant AR splicing variant 7 (ARV7), and AR, in return, regulates the expression of FABP5. Comparisons of the RNA profiles revealed the existence of numerous differentially expressed genes (DEGs) comparing between the parental and the FABP5‑ or AR‑KO cells. The six most abundant changes in DEGs were found to be attributable to the transition from androgen‑responsive to androgen‑unresponsive, castration‑resistant prostate cancer (CRPC) cells. These findings have provided novel insights into the complex molecular pathogenesis of CRPC cells, and have demonstrated that interactions between FABP5 and AR contribute to the transition of prostate cancer cells to an androgen‑independent state. Moreover, gene enrichment analysis revealed that the most highly enriched biological processes associated with the DEGs included those responsive to fatty acids, cholesterol and sterol biosynthesis, as well as to lipid and fatty acid transportation. Since these pathways regulated by FABP5 or AR may be crucial in terms of transducing signals for cancer cell progression, targeting FABP5, AR and their associated pathways, rather than AR alone, may provide a new avenue for the development of therapeutic strategies geared towards suppressing the malignant progression to CRPC cells.

Dataset Information

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

Publications

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

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