PPAR-delta promotes survival of chronic lymphocytic leukemia cells in energetically unfavorable conditions

Abstract

Targeting the mechanisms that allow chronic lymphocytic leukemia (CLL) cells to survive in harsh cancer microenvironments should improve patient outcomes. The nuclear receptor peroxisome proliferator activated receptor delta (PPARδ) sustains other cancers, and in silico analysis showed higher PPARD expression in CLL cells than normal lymphocytes and other hematologic cancers. A direct association was found between PPARδ protein levels in CLL cells and clinical score. Transgenic expression of PPARδ increased the growth and survival of CD5 Daudi cells and primary CLL cells in stressful conditions including exhausted tissue culture media, low extracellular glucose, hypoxia and exposure to cytotoxic drugs. Glucocorticoids and synthetic PPARδ agonists up-regulated PPARD expression and also protected Daudi and primary CLL cells from metabolic stressors. Survival in low glucose was related to increased antioxidant expression, substrate utilization and mitochondrial performance, and was reversed by genetic deletion and synthetic PPARδ antagonists. These findings suggest PPARδ conditions CLL cells to survive in harsh microenvironmental conditions by reducing oxidative stress and increasing metabolic efficiency. Targeting PPARδ may be beneficial in the treatment of CLL.

Quantification of Differential Transcription Factor Activity and Multiomics-Based Classification into Activators and Repressors: <i>DiffTF</i>

“…which coactivate NF-kB-dependent survival signaling in CLL (Minami et al, 2010) and the GATA family, known to prime hematopoietic stem cells (HSCs) toward the lymphoid lineage and to increase self-renewal of the stem cells in CLL (Kikushige et al, 2011). We also found the EGR family, which are implicated in aberrantly hypomethylated CpG sites in CLL (Oakes et al, 2016); Gli1, which is part of the Hedgehog signaling pathway that regulates apoptosis, thereby supporting survival of M-CLL cells (Kern et al, 2015); and PPARD, which has recently been linked to M-CLL through its effect on metabolic pathways in cancer cells (Li et al, 2017). Among the factors that have not previously been associated with CLL we found several TFs significantly higher in U-CLL that are involved in the regulation of the circadian clock (i.e., BMAL1, CLOCK, and NR1D1), which has recently been proposed as a hallmark of cancer (El-Athman and Reló gio, 2018).…”

Induction of apoptosis in prostate cancer by ginsenoside Rh2

“…Regarding PPAR-delta, it was reported that genetic knockdown of the receptor promotes colon cancer growth by decreasing differentiation, increasing proliferation and vascular endothelial growth factor expression in cancer cells [ 24 ]. The receptor could also promote breast cancer and leukemic cell survival cultured under unfavorable metabolic conditions [ 25 , 26 ]. Contrary to these reported PPAR-delta oncogenic effects, studies have also shown possible tumor suppression actions by PPAR-delta.…”

The Involvement of PPARs in the Peculiar Energetic Metabolism of Tumor Cells

“…Various kinds of harsh conditions were tested: low glucose, hypoxia, exposure to glucocorticoids, and cytotoxic agents. In any case, the response of tumor cells was to improve antioxidant activity and make better use of energy supplies through a proper metabolic pathway [ 186 ]. More recently, the involvement of PPARβ/δ signaling in the survival of CLL cell lines was reported.…”