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Xiaoliang L. Xu, Renbing Jia, Hongyan Huang, Walter Joseph, Nengyi Zhou, David H. Abramson, Xianqun Fan, Suresh C. Jhanwar; RXRG Agonist Bexarotene Suppresses Retinoblastoma Growth by Enhancing TRB1 and p53 Tumor Suppressor Activity. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6870.
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© ARVO (1962-2015); The Authors (2016-present)
RB1 is often mutated in retinoblastoma, but is hyperphosphorylated in KRAS mutant cancers. We previously reported that thyroid hormone receptor beta 2 (TRB2) and RXRG were important in retinoblastoma tumorigenesis, and more recently found they may regulate Phospho-Rb, TRB2, and Emi1 based S phase-associated complex (SPC), which was essential for S-phase progression, but it suppressed G2-M transition. In this study, we try to clarify the RXRG role in the cell cycle control and targeted therapy of these cancers.
RXRG was knocked down in retinoblastoma to check cell signaling changes. Retinoblastoma and KRAS mutated tumor cells were also treated with RXRG agonist Bexarotene and antagonist HX531 to check cell growth curve and cell cycle changes. Western blot, real time PCR, and immunofluorescence were utilized to test specific signaling response related to cell cycle and apoptosis. We further tested the therapeutic effect of bexarotene on animal xenograft model of retinoblastoma.
RXRG KD caused SKP2 and PTTG1 activation in retinoblastoma. RXRG agonist bexarotene promoted SPC dissociation by enhancement of TRB1 activity, causing growth suppression in retinoblastoma; whereas RXRG antagonist HX531 prevented TRB2-SPC dissociation by enhancement of TRB2 activity, resulting in growth promotion in retinoblastoma, but not in KRAS mutated cancers. Bexarotene treatment in retinoblastoma caused Emi1 inactivation and SKP2 degradation resulting in S phase arrest. RXRG could also bind to p53, thus Bexarotene treatment could promote p53-targeted gene expression including MDM2, p21, 14-3-3, and GADD45, and p53-mediated apoptosis in retinoblastoma, but not in KRAS-mutated tumors. We found that subconjunctival injection or oral administration of bexarotene could significantly suppress tumor growth in retinoblastoma xenograft model.
RXRG agonist Bexarotene can promote TRB1 and p53 tumor suppressor activity and cause cell cycle arrest and apoptosis in retinoblastoma, but not in KRAS mutated cancers. Retinoblastoma and KRAS mutated cancers have distinct cell cycle signaling and require different treatment strategies.
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