Oncotarget

Research Papers:

Bortezomib-mediated down-regulation of telomerase and disruption of telomere homeostasis contributes to apoptosis of malignant cells

Xinyu Ci, Bingnan Li, Xueping Ma, Feng Kong, Chengyun Zheng, Magnus Björkholm, Jihui Jia and Dawei Xu _

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Oncotarget. 2015; 6:38079-38092. https://doi.org/10.18632/oncotarget.5752

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Abstract

Xinyu Ci1,2,3,4, Bingnan Li3, Xueping Ma1,2,4, Feng Kong1,4, Chengyun Zheng4,5, Magnus Björkholm3,4, Jihui Jia2,4, Dawei Xu3,4

1Central Research Laboratory, Shandong University Second Hospital, Jinan, PR China

2Department of Microbiology, School of Medicine, Shandong University, Jinan, PR China

3Division of Hematology, Department of Medicine and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden

4Karolinska Institutet-Shandong University Collaborative Laboratories for Cancer and Stem Cell Research, Jinan, PR China

5Department of Hematology, Shandong University Second Hospital, Jinan, PR China

Correspondence to:

Dawei Xu, e-mail: Dawei.Xu@ki.se

Jihui Jia, e-mail: jiajihui@sdu.edu.cn

Keywords: apoptosis, BCL2, bortezomib, hTERT, telomerase

Received: August 15, 2015     Accepted: September 30, 2015     Published: October 12, 2015

ABSTRACT

Bortezomib inhibits the ubiquitin/proteasome pathway to achieve its anti-cancer effect and its well characterized activity is the NF-κB inhibition through which the anti-apoptotic bcl-2 expression is down-regulated and apoptosis is subsequently induced. However, the downstream molecular targets of bortezomib are still incompletely defined. Because telomere stabilization via activation of telomerase, induction of telomerase reverse transcriptase (hTERT) and appropriate expression of shelterin proteins is essential to cancer development and progression, we investigated the effect of bortezomib on telomere homeostasis/function in malignant cells. The bortezomib treatment of leukemic (HEL) and gastric cancer cells (BGC-823) led to significant inhibition of hTERT and telomerase expression, widespread dysregulation of shelterin protein expression, and telomere shortening, thereby triggering telomere dysfunction and DNA damage. hTERT over-expression attenuated bortezomib-induced telomere shortening, abnormal shelterin expression and telomere dysfunction. Importantly, bortezomib-mediated apoptosis of malignant cells was partially prevented by hTERT over-expression. Mechanistically, hTERT first robustly enhances bcl2 expression and maintains significantly high residual levels of bcl2 even in bortezomib-treated HEL cells. Second, hTERT protects against bortezomib-induced DNA damage. Our findings collectively reveal a profound impact of bortezomib on telomere homeostasis/function. Down-regulation of hTERT expression and telomere dysfunction induced by bortezomib both contribute to its cancer cell killing actions. It is evident from the present study that hTERT can confer resistance of malignant cells to bortezomib-based target cancer therapy, which may have important clinical implications.


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