Fas-associated protein with death domain (FADD) regulates autophagy through promoting the expression of Ras homolog enriched in brain (Rheb) in human breast adenocarcinoma cells.

Liangqiang He,Jing Zhang,Lu Wang,Zi-Chun Hua,Yunwen Yang,Jie Wang,Hongqin Zhuang,Yongzhe Ren,Rong Zhang,Dianhua Chen,Qianqian Zheng,Shengwen Guan,Wei Cheng,Yueyang Lai,Xiaoxin Zhang

doi:10.18632/oncotarget.8249

Abstract

FADD (Fas-associated protein with death domain) is a classical adaptor protein in apoptosis. Increasing evidences have shown that FADD is also implicated in cell cycle progression, proliferation and tumorigenesis. The role of FADD in cancer remains largely unexplored. In this study, In Silico Analysis using Oncomine and Kaplan Meier plotter revealed that FADD is significantly up-regulated in breast cancer tissues and closely associated with a poor prognosis in patients with breast cancer. To better understanding the FADD functions in breast cancer, we performed proteomics analysis by LC-MS/MS detection and found that Rheb–mTORC1 pathway was dysregulated in MCF-7 cells when FADD knockdown. The mTORC1 pathway is a key regulator in many processes, including cell growth, metabolism and autophagy. Here, FADD interference down-regulated Rheb expression and repressed mTORC1 activity in breast cancer cell lines. The autophagy was induced by FADD deficiency in MCF7 or MDA-231 cells but rescued by recovering Rheb expression. Similarly, growth defect in FADD-knockdown cells was also restored by Rheb overexpression. These findings implied a novel role of FADD in tumor progression via Rheb–mTORC1 pathway in breast cancer.

Highlights

Fas-associated protein with death domain (FADD) is the key adaptor protein transmitting apoptotic signals mediated by death receptors (DRs)
With the help of high-throughput proteomics and bioinformatics analysis, the Ras homolog enriched in brain (Rheb)-mTORC1 pathway was predicted to be dysregulated in human breast adenocarcinoma cell line MCF-7 when FADD was knockdown (Figure 2)
Elevated Rheb expression has been reported in a wide variety of tumors and coupled with mTORC1 hyper-activation, including human breast cancers [34, 57, 58]

Summary

INTRODUCTION

Fas-associated protein with death domain (FADD) is the key adaptor protein transmitting apoptotic signals mediated by death receptors (DRs). We first reported that FADD expression was remarkably higher in breast cancer and applied LC-MS/MS detection plus bioinformatics analysis www.impactjournals.com/oncotarget to reveal that Rheb-mTORC1 pathway was dysregulated in breast cancer cells because of FADD knockdown. To explore the effect of FADD on Rheb-mTORC1 signaling axis, we detected the p70s6k phosphorylation for mTOR activity. The decrease of p70s6k phosphorylation was observed in FADD knockdown cells, which was rescued by recovered Rheb expression. Rheb overexpression could improve cell growth which was retarded for FADD knockdown These data suggest a novel role of FADD in breast tumorigenesis through promoting Rheb expression

RESULTS

DISCUSSION

MATERIALS AND METHODS