SMURF and NEDD4 interference offers therapeutic potential in chaperoning genome integrity.

Farooqi, Ammad Ahmad; Mansoor, Qaisar; Rana, Aamir; Mashhadi, Taskeen Manzoor; Imran, Maryam; Naqi, Syed Ali; Zia-ur-Rehman; Bhatti, Shahzad

Objective: Fusion transcripts had been acclaimed as the hallmark features of hematological malignancies. However, recently these fusion transcripts have been characterized in the prostate cancer epithelial cells. Prostate cancer is a multifactorial anomaly that arises and exacerbates because of miscellany of key mediators instrumental in disease aggressiveness. These chimeric transcripts are cell type specific and therapeutic interventions to address these "lead astray fused genes" are still incompetent and the resultant oncoproteins are considered by conventional approaches as 'undruggable'. Furthermore it is a well established fact that TGF signaling is an important pathway that has broader implication in prostate cancer progression. SMAD proteins are the main effectors which are degraded by negative regulators of TGF signaling. Lack of activator SMADs because of degradation mediated by SMURF and NEDD (ubiquitin ligase) results in genomic instability. Absence of TGF signaling severely abolishes activation of ATM, which is engaged in monitoring faithful repair of genome. DNA damage in absence of ATM relentlessly challenges integrity of genome and results in genomic rearrangements giving rise to hallmark fusion transcript of prostate cancer, i.e. TMPRSS2-ERG. Methods: In this particular study we have used RNA interference technique to unfold the correlation betweeen TGF signaling and fusion transcript appearance in the LNCaP cell line. We have treated the androgen treated and irradiated cell line with siRNA of NEDD4 and SMURF. Results: . There was a successful blockade of both genes at transcriptional level as evidenced by RT PCR study. Simultaneously there was remarkable down regulation in the appearance of fusion transcript. Contrary to this, cells treated with scrambled RNA were insensitive to fusion gene abrogation. Conclusion: The results are indicative of the fact that NEDD4 and SMURF are the major proteins involved in the deviation of core biological systems and combinatorial blockade of these genes or alternatively, drugging negative regulators of TGF pathway will enable us to get a step closer to tailor therapy.

MOLECULAR chaperones; EPITHELIAL cells; PROSTATE cancer treatment; TRANSFORMING growth factors; RNA interference; DISEASE progression

Journal of Experimental & Integrative Medicine, 2011, Vol 1, Issue 1, p43

1309-4572

Academic Journal

10.5455/jeim.030111.or.002