Depletion of CABYR-a/b sensitizes lung cancer cells to TRAIL-induced apoptosis through YAP/p73-mediated DR5 upregulation.

Qianqian Xiao,Mingying Li,Junhao Wang,Jin Liu,Enze Hu,Dacheng He,Weiqing Zhang,Rui Wang,Xiaohua Tan,Fei Kong,Xueyuan Xiao,Jinsan Zhang,Zunlei Qian,Yunguang Li

doi:10.18632/oncotarget.7069

Abstract

Our previous study revealed that knockdown of CABYR-a/b increases the chemosensitivity of lung cancer cells through inactivation of Akt. Here, we demonstrated that depletion of CABYR-a/b significantly increased DR5 expression and sensitized lung cancer cells to TRAIL-induced apoptosis in vitro and/or in vivo. Importantly, treatment with AD5-10, a DR5-specific agonistic monoclonal antibody, was able to mimic TRAIL-induced apoptosis in CABYR-a/b-silenced cells. Strikingly, we identified that depletion of CABYR-a/b not only increased the expressions of p73 and DR5 but also decreased the phosphorylation of YAP S127. Loss- or gain-of-function studies of YAP and p73 revealed that double deletions of YAP and p73 effectively decreased the expression of DR5 and abolished TRAIL-induced apoptosis in CABYR-a/b knockdown cells. Conversely, the co-overexpression of YAP and p73 promoted the expression of DR5 and sensitized cells to TRAIL-induced apoptosis. Taken together, our results demonstrate that depletion of CABYR-a/b sensitizes lung cancer cells to TRAIL-induced apoptosis through YAP/p73-mediated DR5 upregulation.

Highlights

CABYR was first isolated from human spermatozoa and participates in the sperm capacitation
We confirmed that the decrease of aforementioned tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced survival in CABYR-a/b-depleted cells was a result of increased apoptosis as evidenced by Annexin V-PE/7-AAD staining
Knockdown of CABYR-a/b in A549 cells, which have been reported to be resistant to TRAIL treatment [19], increased the TRAIL-induced apoptotic rate more than two-fold compared with sh-vec cells (Figure 1D–1E)

Summary

Introduction

CABYR was first isolated from human spermatozoa and participates in the sperm capacitation. There are six transcript variants of CABYR, which encode five protein isoforms. We verified CABYR as a novel cancer testis antigen in lung cancer [2]. In addition to lung cancer and brain tumors [2,3], CABYR was shown to be aberrantly expressed in liver cancer and esophageal cancer [4]. Knockdown of CABYR-c in HepG2 cells resulted in the inhibition of cell growth [5]. Few studies have evaluated the biological functions of CABYR in cancer cells, with the exception of studies performed in liver and lung cancer cells [4, 6]. The full biological functions of CABYR in cancer cells have yet to be elucidated

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Results

Conclusion