Oncotarget

Research Papers:

Tubulin couples death receptor 5 to regulate apoptosis

Julianne D. Twomey, Liqun Zhao, Shen Luo, Qing Xu, Baolin Zhang _

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Oncotarget. 2018; 9:36804-36815. https://doi.org/10.18632/oncotarget.26407

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Abstract

Julianne D. Twomey1,*, Liqun Zhao1,*, Shen Luo1, Qing Xu1 and Baolin Zhang1

1Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA

*These authors have contributed equally to this work

Correspondence to:

Baolin Zhang, email: Baolin.zhang@fda.hhs.gov

Keywords: tubulin; death receptor 5; TRAIL; apoptosis; cancer therapy

Received: February 09, 2018    Accepted: November 16, 2018    Published: December 04, 2018

ABSTRACT

Activation of death receptor 5 (DR5) to induce apoptosis in cancer cells is an attractive strategy for cancer therapy. However, many tumor cell lines and primary tumors are resistant to DR5 targeted agents including recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and anti-DR5 agonistic antibodies. Here we identify tubulin proteins - primarily consisting of α and β subunits folded into microtubule polymers - as a crucial modulator of DR5 mediated apoptosis. Using affinity purification coupled with mass spectrometry, we found that DR5 interacts with both α- and β-tubulin proteins in cancer cells. Pharmacological disruption of microtubules increased DR5 protein expression and subsequently sensitized the cells to TRAIL-induced apoptosis. Similar results were observed by selectively silencing tubulin transcript using small RNA interference. We also demonstrate that tubulin/microtubule blockade augments TRAIL induced apoptosis by stabilizing DR5 protein. Together, our results link the tubulin/microtubule network to the stringent regulation of DR5 mediated apoptosis, which could lead to potential therapeutic strategies to enhance cancer therapy efficacy.


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