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

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

doi:10.18632/oncotarget.5752

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.

Highlights

The ubiquitin/proteasome system is the major proteolytic site in mammalian cells and plays essential parts in cellular homeostasis and various physiological processes
Bortezomib treatment leads to hTERT, hTER and telomerase down-regulation in malignant cells hTERT and hTER are the core of the telomerase complex and essential to telomerase activity. hTERT expression was previously shown to be down-regulated by bortezomib in subsets of myeloma cell lines [18]
We show a significant impact of bortezomib on telomere homeostasis and function, which may be associated with bortezomib-mediated cancer cell killing activity

Summary

Introduction

The ubiquitin/proteasome system is the major proteolytic site in mammalian cells and plays essential parts in cellular homeostasis and various physiological processes. Bortezomib, as the first proteasome inhibitor for cancer therapy, has www.impactjournals.com/oncotarget proved successful in the treatment of hematological and other malignancies [1,2,3,4,5,6]. It is well-known that bortezomib induces cell death by inhibiting the anti-apoptotic NF-κB signaling pathway whereas enhancing the expression of the pro-apoptotic factor NOXA. Given a broad biological and physiological activity of the proteasome system, bortezomib likely has multiple targets in malignant cells that have not been explored in details. Profound insights into bortezomib-mediated anti-cancer mechanisms should be helpful for its rational application in cancer patients

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