TRAF inhibition drives cancer cell apoptosis and improves retinoic acid sensitivity in multiple cancers models

Author:

Zhong Kun,Liu Xiaojun,Ding Weihua,Peng Lizhong,Zeng Xuhui,Gu Yayun

Abstract

AbstractTNF receptor-associated factors (TRAFs) are signaling adaptor proteins that play a crucial role in regulating cellular receptors’ signaling transduction to downstream pathways and exert multifaceted roles in regulating signaling pathways, cell survival, and carcinogenesis. The 13-cis-retinoic acid (RA), an active metabolite of vitamin A, exhibits anti-cancer properties, but the development of retinoic acid resistance poses a challenge in clinical application. This study aimed to investigate the relationship between TRAFs and retinoic acid sensitivity in various cancers. Here, we revealed that TRAFs’ expression varied significantly across The Cancer Genome Atlas (TCGA) cancer cohorts and human cancer cell lines. Additionally, inhibiting TRAF4, TRAF5, or TRAF6 improved retinoic acid sensitivity and reduced colony formation in ovarian cancer and melanoma cells. Mechanistically, knocking down TRAF4, TRAF5, or TRAF6 in retinoic acid-treated cancer cell lines increased the levels of procaspase 9 and induced cell apoptosis. Further in vivo studies using the SK-OV-3 and MeWo xenograft models confirmed the anti-tumor effects of TRAF knockdown combined with retinoic acid treatment. These findings support that combination therapy with retinoic acid and TRAF silencing may offer significant therapeutic advantages in treating melanoma and ovarian cancers.

Funder

the National Natural Science Foundation of China

the Fundamental Research Funds of Nantong University

the Natural Science Foundation of Jiangsu Province

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Endocrine and Autonomic Systems,Endocrinology,Oncology,Endocrinology, Diabetes and Metabolism

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