Activation of PPARγ by endogenous prostaglandin J2 mediates the antileukemic effect of selenium in murine leukemia

Abstract

Key Points Endogenous CyPG PGJ2 targets LSCs through PPARγ activation. Selenium supplementation could serve as an adjunct therapy for CML.

Endogenus toxicology: Modern physio-pathological aspects and relationship with new therapeutic strategies. An integrative discipline incorporating concepts from different research discipline like Biochemistry, Pharmacology and Toxicology

“…Selenium-dependent activation of PPARγ mediated by endogenous CyPGs decreased Stat5 expression leading to the downregulation of Cited2, a master regulator of LSC quiescence. These studies suggest a potential role for selenium supplementation as an adjuvant therapy in CML" [16].…”

The Regulation of Pathways of Inflammation and Resolution in Immune Cells and Cancer Stem Cells by Selenium

“…Transplantation of these cells leads to disease suggesting that they act as leukemia stem cells (CML-LSCs). Intriguingly, treatment of these cells with selenite (50–500 nM) led to apoptosis that was only restricted to LSCs, while the HSCs expressing GFP were not affected (Finch et al, 2017; Gandhi, et al, 2014; Gandhi, et al, 2011). More importantly, these in-vitro studies corroborated well with in-vivo studies showing similar efficacy towards selenium supplementation on the ablation of LSCs and remission of the disease.…”

“…While the basis of the selectivity of selenium towards LSCs is unclear, our studies show that selenium induces a number of effects in CML-LSCs that could account, in part, for its efficacy and selectivity. These effects include anti-androgen activity, DNA damage-induced response involving ATM-kinase and its downstream effectors such as p53, caspases, p21, and inhibition of anti-apoptotic pathways via the decrease in Mcl1-dependent control of Bcl2 (Finch, et al, 2017; Gandhi, et al, 2014; Sanmartin, Plano & Palop, 2008). Furthermore, p53 activation could also amplify a positive regulatory feedback loop involving long noncoding RNA (lncRNA) that enhances tumor suppressor activity of p53 (Sánchez et al, 2014).…”

“…As introduced in section 1, the extrinsic pathway of LSC control involves monocytes and macrophages that can be reprogrammed with selenium to promote eicosanoid class switching to produce bioactive CyPGs, which are endowed with anti-proliferative activity (Finch, et al, 2017; Gandhi, et al, 2014; Gandhi, et al, 2011). Utilizing conditioned media from bone marrow-derived macrophages (BMDMs), studies have shown that expression of the selenoproteome is critical for eicosanoid class switching to produce CyPGs (Gandhi, et al, 2014; Vunta, et al, 2007).…”

“…However, pioglitazone is associated with side effects that limits it use (Gavrilova et al, 2003; Nesto et al, 2003). Along these lines, a recent study demonstrated the activation PPARγ-dependent signalling in LSCs by selenium led to decreased expression of STAT-5a and its two targets, CITED2 and HIF-2α, which are both known to maintain LSC quiescence (Finch, et al, 2017). Treatment of CML-mice or isolated LSCs with selenium in the presence GW9662, a PPARγ antagonist, blocked the ability of selenium to down-regulate the expression of Stat-5a and its targets leading to leukemia.…”