Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/32863
Title: IDENTIFICATION OF A NOVEL SMALL-MOLECULE PPARGAMMA ACTIVATOR THAT INDUCES AUTOPHAGIC CELL DEATH IN CANCER CELLS
Authors: NG CHUN CHI
Keywords: PPARgamma, activator, autophagy, cell death, cancer cells
Issue Date: 20-Dec-2011
Source: NG CHUN CHI (2011-12-20). IDENTIFICATION OF A NOVEL SMALL-MOLECULE PPARGAMMA ACTIVATOR THAT INDUCES AUTOPHAGIC CELL DEATH IN CANCER CELLS. ScholarBank@NUS Repository.
Abstract: Among the three isoforms of Peroxisome Proliferator-Activated Receptors (PPARs) (gamma, alpha and delta), PPARgamma is the isoform that is most commonly overexpressed in a plethora of cancer cell types. Cancer-specific overexpression of this nuclear receptor has rendered it an attractive therapeutic target. As such, experimental evidence have accrued in the past decade to demonstrate promising antineoplastic effects of PPARgamma agonists, which are represented by the naturally-occurring ligand 15d-PGJ2 and synthetic antidiabetic agents known as the thiazolidinediones (TZDs). These conventional agonists, however, have been historically plagued with safety and potency issues. Moreover, studies using these agents to decipher exact mechanisms of PPARgamma-induced cell cancer death are often confounded by PPARgamma-independent production of ROS. Clinical and experimental limitations of these pre-existing compounds underscore a critical need for identification and development of new-generation PPARgamma activators. Here we identified a novel small molecule PPARgamma activator, named Pr-MPO, which is structurally unrelated to TZDs. Pr-MPO-triggered PPARgamma transcriptional activity was confirmed not only by transfection of reporter constructs containing peroxisome proliferator-response element (PPRE), but also functionally validated by transcriptional modulations of a panel of PPARgamma bona fide gene targets in cancer cells. Pr-MPO was dependent upon PPARgamma expression and transactivation for its antineoplastic effects, and was demonstrated to induce effective cell kill only in PPARgamma-overexpressing cancer cells while exerting minimal effect on their non-PPARgamma-expressing normal counterparts. Even though pre-existing agonists were also shown to exert such anticancer functions, Pr-MPO possesses numerous advantages over these compounds, namely, a prominent improvement in potency, lack of off-target ROS/RNS production, consistent efficacy in different serum conditions, and lastly, the ability to engage a novel death pathway that is not mediated solely by classical apoptosis, but rather dependent on autophagic induction. Indeed, autophagy inhibition by both pharmacological inhibitor 3-methyl-adenine (3-MA) and silencing of autophagy related genes (Atg) restored cancer cell viability, long-term clonogenic abilities and abrogated biochemical hallmarks of apoptosis. Our findings thus support the notion of an alternative death paradigm where autophagy precedes and is casually linked to the subsequent onset of programmed cell death with apoptotic features. The discovery of this physiological effect of Pr-MPO in cancer cells sparked further investigations to delineate a previously unestablished regulatory role of PPARgamma in mounting a coordinated autophagic response that is responsible for cellular demise. In this model, we demonstrate that PPARgamma can act as an integral mediator of autophagy, as evidenced by the dependence of Pr-MPO-induced autophagic cell death upon PPARgamma transcriptional activity. Further studies identified BNIP3, NHE-1 and MnSOD as PPARgamma transcriptional targets acting as molecular links between PPARgamma activation and autophagy induction. Overall, data from our study provide a compelling rationale for Pr-MPO to be developed as a drug candidate or lead compound in cancer therapeutics. Moreover, utilization of Pr-MPO as an experimental tool also reveals a novel approach of cancer-specific autophagy induction, whereby a transcription factor that is selectively overexpressed in cancer is targeted to orchestrate autophagic cell death, in order to circumvent the potential hazard of pharmacologically modulating ubiquitous Atg genes.
URI: http://scholarbank.nus.edu.sg/handle/10635/32863
Appears in Collections:Ph.D Theses (Open)

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