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Original Article

Towards TRAIL to silencing of SMURF and NEDD4: FLIP is flopped

Ammad A. Farooqi, Sundas Fayyaz, Shahzad Bhatti, Muhammad Ismail, Qaisar Mansoor.

Cited by (7)

Prostate cancer is a multifactorial anomaly that arises and exacerbates because of miscellaneous key mediators instrumental in disease aggressiveness. Heterogeneity of the disease offers stumbling blocks in standardization of therapeutic interventions. TRAIL is an endogenous key mediator that has central role in killing neoplastic cells and sparing innocent cells. However this ligand also undergoes a downregulation in prostate carcinogenesis. In this particular study we hypothesized whether abrogation of negative regulators of TGF signaling potentiates the expression of TRAIL or not.
Materials and methods
In this particular study we have used androgen sensitive prostate cancer cell line (LNCaP) and treated it with TGF. TGF treatment was also given to LNCaP cell line. RNA interference technique was used to unfold the correlation betweeen TGF signaling and TRAIL expression in the LNCaP cell line. The results were analyzed by RT PCR.
We have treated the TGF treated cell line with siRNA of NEDD4 and SMURF. There was a successful blockade of both genes at transcriptional level as evidenced by RT PCR study. Simultaneously there was remarkable upregulation in the expression of TRAIL. Another interesting observation was that TGF treatment triggered expression of TRAIL and this activity shifted to a robust activation after abrogation of negative regulators of TGF signal transduction.
In this study, we show that TRAIL expression is upregulated upon exposure of LNCaP cell lines to TGF-β and that TRAIL is a major contributor to apoptosis mediated by TGF-β. Consistent with the interpretations it is obvious that NEDD4 and SMURF are the major proteins involved in the deviation of core biological systems and combinatorial blockade of these genes by rational drug design or alternatively, drugging negative regulators of TGF pathway might offer exciting avenues in translational oncology

Key words: ATM; cFLIP; NEDD4; Prostate cancer; SMURF; TRAIL

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