Abstract
Neuroblastoma is the most common solid extra cranial tumor in infants. Improving the clinical outcome of children with aggressive tumors undergoing one of the multiple treatment options has been a major concern. Differentiating neuroblastoma cells holds promise in inducing tumor growth arrest and treating minimal residual disease. In this study, we investigated the effect of partial PPARγ agonist 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) on human neuroblastoma IMR32 cells. Our results demonstrate that treatment with low concentration of CDDO and particularly in combination with all trans retinoic acid (ATRA) induced neurite outgrowth, increased the percentage of more than two neurites bearing cells, and decreased viability in IMR32 cells. These morphological changes were associated with an increase in expression of bonafide differentiation markers like β3-tubulin and Neuron Specific Enolase (NSE). The differentiation was accompanied by a decrease in the expression of MYCN whose amplification is known to contribute to the pathogenesis of neuroblastoma. MYCN is known to negatively regulate NMYC downstream-regulated gene 1 (NDRG1) in neuroblastomas. MYCN down-regulation induced by CDDO correlated with increased expression of NDRG1. CDDO decreased Anaplastic Lymphoma Kinase (ALK) mRNA expression without affecting its protein level, while ATRA significantly down-regulated ALK. Antagonism of PPARγ receptor by T0070907 meddled with differentiation inducing effects of CDDO as observed by stunted neurite growth, increased viability and decreased expression of differentiation markers. Our findings indicate that IMR32 differentiation induced by CDDO in combination with ATRA enhances, differentiation followed by cell death via cAMP-response-element binding protein (CREB) independent and PPARγ dependent signaling mechanisms.
Highlights
Cell fate determination and differentiation are processes that are crucial in developmental biology, which assigns cells their functional roles and gives them unique identity
A dose response experiment was performed with various concentrations of a known differentiation inducer, i.e., all trans retinoic acid (ATRA) (5, 7.5, 10, and 15 μM) and it revealed that ATRA 10 and 15 μM induced neurite outgrowth
IMR32 cells were treated with 0.7 μM CDDO individually, and in combination with 10 μM ATRA for 5 days to check the combinatorial effect
Summary
Cell fate determination and differentiation are processes that are crucial in developmental biology, which assigns cells their functional roles and gives them unique identity. It is a result of differential gene expression, epigenetic modifications, ceased proliferation, and morphological changes converting the precursor cells to specialized ones. PPARγ Signaling Is Involved in IMR32 Differentiation committed to a specific lineage (Slack, 2012). In 1971, Barry Pierce and Carol Wallace had put forward a proof of concept that certain malignant cells can differentiate into benign cells. Evidence from their research on squamous cell carcinoma supports the idea that a progeny of malignant stem cells can differentiate into post-mitotic benign squamous cells incapable of forming a tumor (Pierce and Wallace, 1971)
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