Fatty acid-binding protein 5 (FABP5)-related signal transduction pathway in castration-resistant prostate cancer cells: a potential therapeutic target

In this short communication, a novel fatty acid-binding protein 5 (FABP5)-related signal transduction pathway in prostate cancer is reviewed. In castration-resistant prostate cancer (CRPC) cells, the FABP5-related signal transduction pathway plays an important role during transformation of the cancer cells from androgen-dependent state to androgen-independent state. The detailed route of this signal transduction pathway can be described as follows: when FABP5 expression is increased as the increasing malignancy, excessive amounts of fatty acids from intra- and extra-cellular sources are transported into the nucleus of the cancer cells where they act as signalling molecules to stimulate their nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ). The phosphorylated or biologically activated PPARγ then modulates the expression of its downstream target regulatory genes to trigger a series of molecular events that eventually lead to enhanced tumour expansion and aggressiveness caused by an overgrowth of the cancer cells with a reduced apoptosis and an increased angiogenesis. Suppressing the FABP5-related pathway via RNA interference against FABP5 has produced a 63-fold reduction in the average size of the tumours developed from CRPC cells in nude mice, a seven-fold reduction of tumour incidence, and a 100% reduction of metastasis rate. Experimental treatments of CRPC with novel FABP5 inhibitors have successfully inhibited the malignant progression of CRPC cells both in vitro and in nude mouse. These studies suggest that FABP5-related signal transduction pathway is a novel target for therapeutic intervention of CRPC cells

Molecular mechanisms on how FABP5 inhibitors promote apoptosis-induction sensitivity of prostate cancer cells.

Previous work showed that FABP5 inhibitors suppressed the malignant progression of prostate cancer cells, and this suppression might be achieved partially by promoting apoptosis. But the mechanisms involved were not known. Here, we investigated the effect of inhibitors on apoptosis and studied the relevant mechanisms. WtrFABP5 significantly reduced apoptotic cells in 22Rv1 and PC3 by 18% and 42%, respectively. In contrast, the chemical inhibitor SB-FI-26 produced significant increases in percentages of apoptotic cells in 22Rv1 and PC3 by 18.8% (±4.1) and 4.6% (±1.1), respectively. The bio- inhibitor dmrFABP5 also did so by 23.1% (±2.4) and 15.8% (±3.0), respectively, in these cell lines. Both FABP5 inhibitors significantly reduced the levels of the phosphorylated nuclear fatty acid receptor PPARγ, indicating that these inhibitors promoted apoptosis-induction sensitivity of the cancer cells by suppressing the biological activity of PPARγ. Thus, the phosphorylated PPARγ levels were reduced by FABP5 inhibitors, the levels of the phosphorylated AKT and activated nuclear factor kapper B (NFκB) were coordinately altered by additions of the inhibitors. These changes eventually led to the increased levels of cleaved caspase-9 and cleaved caspase-3; and thus, increase in the percentage of cells undergoing apoptosis. In untreated prostate cancer cells, increased FABP5 suppressed the apoptosis by increasing the biological activity of PPARγ, which, in turn, led to a reduced apoptosis by interfering with the AKT or NFκB signaling pathway. Our results suggested that the FABP5 inhibitors enhanced the apoptosis-induction of prostate cancer cells by reversing the biological effect of FABP5 and its related pathway

FABP5 can substitute for androgen receptor in malignant progression of prostate cancer cells.

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

Experimental treatment efficacy of dmrFABP5 on prostate cancer singly or in combination with drugs in use.

Enzalutamide is a drug used to treat prostate cancer (PC) and docetaxel is a drug for chemotherapeutic treatment of diverse cancer types, including PC. The effectiveness of these drugs in treating castration-resistant prostate cancer (CRPC) is poor and therefore CRPC is still largely incurable. However, the bio-inhibitor of fatty acid-binding protein 5 (FABP5), dmrFABP5, which is a mutant form of FABP5 incapable of binding to fatty acids, has been shown recently to be able to suppress the tumorigenicity and metastasis of cultured CRPC cells. The present study investigated the possible synergistic effect of dmrFABP5 combined with either enzalutamide or docetaxel on suppressing the tumorigenic properties of PC cells, including cell viability, migration, invasion and colony proliferation in soft agar. A highly significant synergistic inhibitory effect on these properties was observed when dmrFABP5 was used in combination with enzalutamide on androgen-responsive PC 22RV1 cells. Moreover, a highly significant synergistic inhibitory effect was also observed when dmrFABP5 was combined with docetaxel, and added to 22RV1 cells and to the highly malignant, androgen-receptor (AR)-negative Du145 cells. DmrFABP5 alone failed to produce any suppressive effect when added to the FABP5-negative cell line LNCaP, although enzalutamide could significantly suppress LNCaP cells when used as a single agent. These synergistic inhibitory effects of dmrFABP5 were produced by interrupting the FABP5-related signal transduction pathway in PC cells. Thus, dmrFABP5 appears to be not only a potential single therapeutic agent, but it may also be used in combination with existing drugs to suppress both AR-positive and AR-negative PC

Morphometric Analysis of the Midline Mandibular Lingual Canal and Mandibular Lingual Foramina: A Cone Beam Computed Tomography (CBCT) Evaluation

Background: This study aimed to evaluate the midline mandibular lingual canals and foramina and their anatomic variations using CBCT scans. Methods: This study used retrospective analysis. A total of 320 CBCT scans were used to evaluate the study parameters, which comprised the presence or absence of the mandibular lingual foramen (MLF)/mandibular lingual canal (MLC) and its category, the distance between the buccal cortex and the start of the MLC, the distance between the inferior border of the mandible and the superior border of the foramen at its lingual and buccal terminals. The length and diameter of each canal at its lingual and buccal terminals. Results: MLC was found in all included CBCT scans. Out of 320 included CBCT scans, a single canal was represented by 30.9%, double canals (Supra with Infra -spinosum) configuration appeared in 54.7%, and triple canals (Supra-Inter-Infra) represented 14.7%. The supraspinosum canals averaged 5.81 ± 2.08 mm in length and 0.87 ± 0.30 mm in diameter at the lingual terminal. In terms of the number of canals, there was a significant difference between men and women (p ≤ 0.001), with 60% of the men in the sample having double canals and 43.1% of the women having single canals. Moreover, the male gender had a higher prevalence of triple canals (21.3% vs. 8.1%) than females. Males and females were distributed equally among the supraspinosum canals, with no statistically significant difference (p ≤ 0.7). A considerable increase in the finding of interspinosum and infraspinosum canals was seen in the male sample (p ≤ 0.001). Conclusions: midline mandibular canals were found in all investigated CBCTs of the sample of both sexes; however, the anatomy and location of the MLF and canals varied significantly among the Saudi population