Peroxisome proliferator‐activated receptor‐β/δ inhibits human neuroblastoma cell tumorigenesis by inducing p53‐ and SOX2‐mediated cell differentiation

Abstract

Neuroblastoma is a common childhood cancer typically treated by inducing differentiation with retinoic acid (RA). Peroxisome proliferator-activated receptor-β/δ, (PPARβ/δ) is known to promote terminal differentiation of many cell types. In the present study, PPARβ/δ was over-expressed in three human neuroblastoma cell lines, NGP, SK-N-BE(2), and IMR-32, that exhibit high, medium, and low sensitivity, respectively, to retinoic acid-induced differentiation to determine if PPARβ/δ and retinoic acid receptors (RARs) could be jointly targeted to increase the efficacy of treatment. All-trans-RA (atRA) decreased expression of SRY (sex determining region Y)-box 2 (SOX2), a stem cell regulator and marker of de-differentiation, in NGP and SK-N-BE(2) cells with inactive or mutant tumor suppressor p53, respectively. However, atRA did not suppress SOX2 expression in IMR-32 cells carrying wild-type p53. Over-expression and/or ligand activation of PPARβ/δ reduced the average volume and weight of ectopic tumor xenografts from NGP, SK-N-BE(2), or IMR-32 cells compared to controls. Compared with that found with atRA, PPARβ/δ suppressed SOX2 expression in NGP and SK-N-BE(2) cells and ectopic xenografts, and was also effective in suppressing SOX2 expression in IMR-32 cells that exhibit higher p53 expression compared to the former cell lines. Combined, these observations demonstrate that activating or over-expressing PPARβ/δ induces cell differentiation through p53- and SOX2-dependent signaling pathways in neuroblastoma cells and tumors. This suggests that combinatorial activation of both RARα and PPARβ/δ may be suitable as an alternative therapeutic approach for RA-resistant neuroblastoma patients.

PPARδ Elicits Ligand-Independent Repression of Trefoil Factor Family to Limit Prostate Cancer Growth

“…antagonizing PPARd inhibits tumorigenesis in lung, liver, breast, or prostate cell lines (29)(30)(31). Conversely, various studies have demonstrated that the activation of PPARd by agonists reverts or inhibits tumorigenesis in colorectal, liver, skin, breast, testicular, pancreatic cancer, or neuroblastoma cells (32)(33)(34)(35)(36)(37)(38)(39), in line with the notion that the deregulation of this nuclear receptor promotes oncogenesis in Ppard-deficient mice and colorectal cancer cells (40,41). The expression status of PPARd in cancer has been evaluated by different groups with contrasting results, which may be related to the tissue of origin and the method for quantification of PPARD levels (42)(43)(44).…”

Induction of apoptosis in prostate cancer by ginsenoside Rh2

“…Contrary to these reported PPAR-delta oncogenic effects, studies have also shown possible tumor suppression actions by PPAR-delta. Inhibition of cell proliferation by PPAR-delta ligands were demonstrated in a number of tumors including lung cancer, colon cancer and neuroblastoma [ 27 – 29 ]. Therefore the role of PPAR-delta in cancer treatment is still controversial.…”

Neuroblastoma: Genetic, Epigenetic Mechanisms and Targeted Therapy Approaches: Review

“…79 PPARD' nin, hücre farklılaşmasını düzenleyen ve kullanılmakta olan terapide rol alan RARA ile koaktivasyonu, nö-roblastların normal diferansiyasyonunu sağlayarak nöroblastom tedavisinde yeni bir kombinasyonel yaklaşım oluşturmaktadır. 80 ALK ve CDK4/6; AURKA ve BCL2' nin dual inhibisyonları da nö-roblastom tedavisinde sinerjistik yaklaşımlar oluş-turmaktadır. [81][82][83] Epigenetik regülasyon, nöroblastomun patogenezinde olduğu kadar tedavide de büyük önem taşımaktadır.…”