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Biomed Pharmacother. 2016 Feb;77:108-13. doi: 10.1016/j.biopha.2015.12.010. Epub 2015 Dec 29.

The molecular mechanisms of XBP-1 gene silencing on IRE1α-TRAF2-ASK1-JNK pathways in oral squamous cell carcinoma under endoplasmic reticulum stress.

Author information

1
Oral Maxillofacial Head-Neck Key Laboratory of Medical Biology, and Central Laboratory of Liaocheng People's Hospital, Shandong 252000, China; Department of Pharmacy, Liaocheng University, Shandong 252000, China.
2
Oral Maxillofacial Head-Neck Key Laboratory of Medical Biology, and Central Laboratory of Liaocheng People's Hospital, Shandong 252000, China.
3
Department of Oral and Maxillofacial Surgery, Liaocheng People's Hospital, Shandong 252000, China.
4
Department of Oral and Maxillofacial Surgery, Liaocheng People's Hospital, Shandong 252000, China. Electronic address: Bin_zhanglc@yahoo.com.cn.
5
School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW 2650, Australia. Electronic address: lwang@csu.edu.au.

Abstract

BACKGROUND:

Proteasome inhibitor Carbobenzoxy-Leu-Leu-leucinal (MG132) induces the unfolded protein response (UPR) in oral squamous cell carcinoma (OSCC). X-box binding protein 1 (XBP1) is a key UPR component that regulates endoplasmic reticulum stress (ER) homeostasis. This study was aimed to investigate the activation of IRE1α-TRAF2-ASK1-JNK pathway by silencing the XBP1 expression in an OSCC cell line.

METHODS:

The XBP1 specific short hairpin RNA (shRNA) plasmid vector was constructed and then transfected into the Tca-8113 cells. The effect of XBP-1 gene silencing on IRE1α-TRAF2-ASK1-JNK pathway under MG132 induced endoplasmic reticulum stress in Tca-8113 were investigated by real-time RT-PCR or western blot. Cell apoptosis was detected by flow cytometry.

RESULTS:

XBP1 expression was reduced in transfected groups and MG132 groups. shRNA-XBP1 induces IRE1α-TRAF2-ASK1 signaling activation to activate pro-apoptotic ASK1-JNK signaling. Moreover, combined shRNA-XBP1 with MG132 further enhanced downregulated XBP1 expression and upregulated activation of ASK1-JNK signaling.

CONCLUSIONS:

Silencing XBP1 expression under MG132 induced ER stress block the XBP1 survival pathway and synergism with MG132 to promote Tca8113 cell apoptosis. These findings provide a therapeutic option in oral squamous cell carcinoma by inhibition of proteasome and XBP1 splicing.

KEYWORDS:

Apoptosis; MG132; Oral squamous cell carcinoma; Silencing; X-box binding protein 1

PMID:
26796273
DOI:
10.1016/j.biopha.2015.12.010
[Indexed for MEDLINE]

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