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.
Highlights
Death receptor-5 (DR5), known as tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptor 2 (TRAIL-R2), is a cell surface receptor of the tumor necrosis factor (TNF)-receptor superfamily that contains a cytoplasmic death domain [1]
Using affinity purification coupled with mass spectrometry, we found that death receptor 5 (DR5) interacts with both α- and β-tubulin proteins in cancer cells
Given the known functions of tubulins in apoptosis, we focused on characterization of tubulinDR5 interaction
Summary
Death receptor-5 (DR5), known as TRAIL receptor 2 (TRAIL-R2), is a cell surface receptor of the TNF-receptor superfamily that contains a cytoplasmic death domain [1] This receptor transduces apoptotic signals from its physiological ligand – tumor necrosis factor-related apoptosis inducing ligand (TRAIL) – or its agonistic antibodies [2]. The underlying mechanisms remain incompletely defined; the deficiency in DR5 itself does play a role in rendering cancer resistance to DR5 targeted therapy [7,8,9,10,11] In this regard, DR5 has been shown to undergo rapid internalization in a ligand-dependent manner [8, 12] and sequester into intracellular compartments such as the nucleus [9] or autophagosome vesicles [10], leading to its absence on the surface membrane of targeted cells
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