RXR? provokes tumor suppression through p53/p21/p16 and PI3K-AKT signaling pathways during stem cell differentiation and in cancer cells.

ABSTRACT: The retinoid X receptor alpha (RXR?) is an important therapeutic target impacting diverse biological processes. Activation of RXR? is known to suppress cancer cell growth. However, the cellular mechanism has been elusive. In the present study, we addressed its role during stem cell differentiation and the underlying connections with carcinogenesis. RXR? was significantly upregulated following the differentiation of human mesenchymal stem cell (hMSC) toward the formation of endothelial cell (EC). However, overexpression of RXR? in hMSC provoked a senescence-like phenotype accompanied by the elevation of tumor suppressor p53, p21, and p16. Consistently, RXR? level was suppressed in cancer cells (~five times lower compared to differentiated hMSC), and its elevation could inhibit the proliferation, migration, and angiogenesis of cancer cells. We further demonstrated that these inhibitory effects were related to RXR?'s interaction with estrogen receptor ? (ER?) as well as EGF and ANGPTL3 through modulating PI3K/AKT signaling pathway by AKT and FAK phosphorylation. Moreover, RXR? inhibited glycolytic metabolism in cancer cells, which might be underlying its inhibition of differentiation and carcinogenic features. These data suggest that RXR? acts as a suppressor rather than a driving force during stem cell differentiation, and unbalanced RXR? can trigger multiple yet connected signaling pathways in preventing carcinogenesis.

SUBMITTER: Zhang R 

PROVIDER: S-EPMC5945609 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature