4 results on '"Bhatti, Shahzad"'
Search Results
2. Fusion transcripts: hopes and pitfalls in tranquilizing the trouble mongers in prostate cancer.
- Author
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Farooqi, Ammad A. and Bhatti, Shahzad
- Subjects
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PROSTATE cancer , *CHROMOSOMAL proteins , *ANDROGEN receptors , *DISEASE exacerbation , *GENOMICS - Abstract
Prostate cancer is a multifactorial disease. It harbours a miscellany of fusion transcripts originating from chromosomal rearrangements. Additionally, susceptibility to genomic rearrangements is particularly enhanced in prostate cancer which is triggered by androgen. These fusion transcripts hijack the promoters of androgen regulated genes and exploit them for triggering anomalies. These chimeric transcripts vary in various cancer foci. A complex barcode underlies the heterogeneous response of these entities to stress. Nonetheless these transcripts create a formidable state of affairs within the cell. Exacerbation of the disease which is mediated by fusion transcripts culminates into a poor survival. Currently there are unsatisfactory and inefficient measures to circumscribe this rapidly growing threat. The review will encompass various mechanistic insights of the androgen receptor mediated genomic instability and the mediators entailed in rendering cell error prone. Moreover efficacy of therapeutic interventions recently designed keeping in view the molecular hierarchy will be evaluated. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
3. Towards TRAIL to silencing of SMURF and NEDD4: FLIP is flopped.
- Author
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Farooqi, Ammad Ahmad, Fayyaz, Sundas, Bhatti, Shahzad, Ismail, Muhammad, and Mansoor, Qaisar
- Subjects
PROSTATE cancer ,DISEASE exacerbation ,STANDARDIZATION ,HETEROGENEITY ,CANCER cells - Abstract
Objective: 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 and cFLIP are two diametrically opposed key mediators that antagonize each others function. TRAIL 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 and abolishes the expression of TRAIL and cFLIP respectively or not. Methods: In this particular study we have used androgen sensitive prostate cancer cell line (LNCaP) and treated it with TGF and etoposide. RNA interference technique was used to unfold the correlation betweeen TGF signaling and TRAIL and cFLIP expression in the LNCaP cell line. Enforced expression of SMURF and NEDD4 was done by transfecting cell line with respective constructs. The results were analyzed by RT-PCR and western blot. Results: We have treated the TGF and etoposide 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 ablated cFLIP and this activity was pronounced after abrogation of negative regulators of TGF signal transduction. Further investigation into the molecular mechanism was done by reconstitution of SMURF and NEDD4 depleted LNCaP cells which resulted in an enhanced expression of cFLIP. Conclusion: In this study, we show that TRAIL expression is upregulated and cFLIP is downregulated upon exposure of LNCaP cell lines to TGF-β and etoposide 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. Combinatorial blockade of these genes by rational drug design, or alternatively, drugging negative regulators of TGF pathway might offer exciting avenues in key aspects of the science of therapeutic individualization. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
4. SMURF and NEDD4 interference offers therapeutic potential in chaperoning genome integrity.
- Author
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Farooqi, Ammad Ahmad, Mansoor, Qaisar, Rana, Aamir, Mashhadi, Taskeen Manzoor, Imran, Maryam, Naqi, Syed Ali, Zia-ur-Rehman, and Bhatti, Shahzad
- Subjects
MOLECULAR chaperones ,EPITHELIAL cells ,PROSTATE cancer treatment ,TRANSFORMING growth factors ,RNA interference ,DISEASE progression - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
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