Research On Mechanism Of Cell Cycle Arrest And Growth Inhibition Induced By Specific RARA Agonist In T Cell Lymphoma By Targeting CDK6/4 Pathway

T cell lymphoma are aggressive and heterogenetic non-Hodgkin lymphomas.Outcomes are poor even following standard chemotherapy regimens,suggesting that finding new target drugs is critical to improve outcomes of these tumors.Retinoic acid(RA)has been approved for the treatment of cutaneous T cell lymphoma,yet response rates to RA in T cell lymphoma are limited and mechanism is still unclear.RARA is a type II nuclear receptor,and can drive cell differentiation and cell growth by recognizing RA.Our group found RARA R394 Q mutation in T cell lymphoma case by Next-Generation Sequencing.The goal of this study is to explore the effect and mechanism of RARA in T cell lymphoma.Firstly,we classified T cell lymphoma cell lines into either RARA high-expressed cell lines(Mac-1 cell)or RARA low-expressed cell lines(Hut78 cell and Karpas299 cell)based on RARA protein expression by western blot.We detected cell growth and cell cycle of these cells in response to all-trans retinoic acid and RARA relatively sensitive agonist AM80 by MTT method and PI staining.Our data display that the sensitivity of tumor cell lines to RA is increased with higher RARA expression(Mac-1 cell).RARA overexpression increased RA sensitivity and cell growth in Hut78 and Karpas299 cells with low RARA protein expression.SiRARA in Mac-1 cells decreased cell growth and induced G1 arrest possibly by down up-regulating CDK6/4 expression.RA treatment in cells with native high or overexpressed RARA protein further induced RARA degradation,CDK6/4 down regulation and G1 phase arrest with RARA agonist or SiRARA can induced G1 arrest and cell growth inhibition by down-regulating RARA expression,and further CDK6/4 expressions.These data indicate that RARA could be potential target for T cell lymphoma treatment.