Abstract
BackgroundFGD4 (Frabin) is an F-actin binding protein with GTP/GDP exchange activity specific for CDC42. It is involved in reorganization of the actin cytoskeleton, which requires both actin binding and CDC42 activating function of FGD4. Expression of FGD4 is altered in patients with heterogeneous hereditary motor and sensory neuropathies as a result of demyelination of peripheral nerves.MethodsIn this study, we examined the expression of FGD4 in prostate cancer specimens using immunohistochemistry and studied the function of FGD4 in maintaining cell phenotype, behavior and drug sensitivity using overexpression and siRNA-based silencing approaches. We used Mann-Whitney test for comparative analysis of FGD4 expression.ResultsOur results show that the expression of FGD4 is upregulated in cancerous prostates compared to the luminal cells in benign prostatic hyperplasia, although the basal cells showed high staining intensities. We noted a gradual increase in the staining intensity of FGD4 with increasing aggressiveness of the disease. Inhibition of expression of FGD4 using siRNAs showed reduced proliferation and cell cycle arrest in G2/M phase of androgen dependent LNCaP-104S and androgen refractory PC-3 cells. Inhibition of FGD4 also resulted in reduced cell migration and CDC42 activities in PC-3 cells whereas, ectopic expression of FGD4 induced cell migration, altered expression of mesenchymal and epithelial markers and activation of CDC42/PAK signaling pathway. Reduced expression of FGD4 improved sensitivity of LNCaP-104S cells to the anti-androgen drug Casodex and PC-3 cells to the microtubule stabilizing drug docetaxel.ConclusionsOur data demonstrate a tumor promoting and a cell migratory function of FGD4 in prostate cancer cells and that inhibition of FGD4 expression enhances the response for both androgen-dependent and independent prostate cancer cells towards currently used prostate cancer drugs.
Highlights
FGD4 (Frabin) is an F-actin binding protein with GTP/GDP exchange activity specific for CDC42
We confirmed that FGD4 is one of the targets of miR-17 and -20a from this cluster and is upregulated in Casodex resistant prostate cancer cells [32, 36]
A moderately strong staining was noted in the basal cells and in the stromal areas in PIN (H) lesions (Fig. 1a and b), whereas a moderate to strong staining was noted in the cytoplasm of carcinomas
Summary
FGD4 (Frabin) is an F-actin binding protein with GTP/GDP exchange activity specific for CDC42. It is involved in reorganization of the actin cytoskeleton, which requires both actin binding and CDC42 activating function of FGD4. FGD4, a guanine nucleotide exchange factor (GEF) specific for CDC42 Rho GTPase, is an F-actin binding protein [1] which is essential for maintenance of myelination in Schwann cells [2]. Each contain an FYVE domain in addition to a Dbl homology (DH) domain for catalytic activity and two pleckstrin homology (PH) domains for targeting proteins to the membrane through phosphoinositide binding [3,4,5].
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