Inhibition of Doxorubicin-Induced Senescence by PPARδ Activation Agonists in Cardiac Muscle Cells: Cooperation between PPARδ and Bcl6

Abstract

Senescence and apoptosis are two distinct cellular programs that are activated in response to a variety of stresses. Low or high doses of the same stressor, i.e., the anticancer drug doxorubicin, may either induce apoptosis or senescence, respectively, in cardiac muscle cells. We have demonstrated that PPARδ, a ligand-activated transcriptional factor that controls lipid metabolism, insulin sensitivity and inflammation, is also involved in the doxorubicin-induced senescence program. This occurs through its interference with the transcriptional repressor protein B cell lymphoma-6 (Bcl6). Low doses of doxorubicin increase the expression of PPARδ that sequesters Bcl6, thus preventing it from exerting its anti-senescent effects. We also found that L-165041, a specific PPARδ activator, is highly effective in protecting cardiomyocytes from doxorubicin-induced senescence through a Bcl6 related mechanism. In fact, L-165041 increases Bcl6 expression via p38, JNK and Akt activation, and at the same time it induces the release of Bcl6 from PPARδ, thereby enabling Bcl6 to bind to its target genes. L-165041 also prevented apoptosis induced by higher doses of doxorubicin. However, while experiments performed with siRNA analysis techniques very clearly showed the weight of Bcl6 in the cellular senescence program, no role was found for Bcl6 in the anti-apoptotic effects of L-165041, thus confirming that senescence and apoptosis are two very distinct stress response cellular programs. This study increases our understanding of the molecular mechanism of anthracycline cardiotoxicity and suggests a potential role for PPARδ agonists as cardioprotective agents.

p66Shc signaling is involved in stress responses elicited by anthracycline treatment of rat cardiomyoblasts

“…The objective of this work was to investigate the involvement of p66Shc signaling in DOX-induced stress responses in H9c2 cardiomyoblasts (Altieri et al 2012;Spallarossa et al 2009). Because DOX treatment induces cardiac oxidative stress, which was previously confirmed by us in our cell model (Sardao et al 2009a), we hypothesize that this results in the activation of a positive feedback loop involving p66Shc translocation to the mitochondrial fraction and further generation of local oxidative stress.…”

Peroxisome Proliferator-Activated Receptor δ Agonist, HPP593, Prevents Renal Necrosis under Chronic Ischemia

“…In these studies the cytoprotective role of PPARδ has been linked to suppression of inflammation. Two primary mechanisms, by which activated, agonist-bound PPARδ modulates inflammatory signaling have been found: i) deactivation of nuclear factor NF-κB complex via interaction with the p65 subunit [93]; ii) release of the transcriptional repressor Bcl6 (B cell lymphoma-6) from its complex with PPARδ [94], [95], [96]. These two mechanisms of PPARδ action, together with PPARδ-dependent up regulation of oxidative stress defense genes, are likely to contribute to attenuation of oxidative stress in kidneys of HPP593-treated 2K1C rats [59], [97].…”

Doxorubicin anti-tumor mechanisms include Hsp60 post-translational modifications leading to the Hsp60/p53 complex dissociation and instauration of replicative senescence

“…Cell growth was not inhibited after 24,48, and 72 h (data not shown) but clear effects were observed after a five-day exposure to doxorubicin. A dose-dependent reduction of cell viability was evident as shown by MTT (Fig.…”

“…For example, doxorubicin, an anthracycline antitumor drug widely used in clinical chemotherapy, induces senescence at low doses and apoptosis at high doses in breast cancer cells and in neonatal rat cardiomyocytes [24,25,26]. Hsp60 over-expression suppressed doxorubicin-induced apoptosis in cardiomyocytes [27], and doxorubicin-induced apoptosis in HeLa cells triggering Hsp60 up-regulation [23].…”