Mitochondrial inhibitor sensitizes non-small-cell lung carcinoma cells to TRAIL-induced apoptosis by reactive oxygen species and Bcl-X(L)/p53-mediated amplification mechanisms.

Y-L Shi,W Chen,W Yin,J-J Bian,Z-C Hua,S Feng

doi:10.1038/cddis.2014.547

Y-L Shi, W Chen + Show 4 more

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https://doi.org/10.1038/cddis.2014.547

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Journal: Cell Death & Disease	Publication Date: Dec 1, 2014
Citations: 22	License type: CC BY 4.0

Affiliation: Nanjing University

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for anticancer therapy; however, non-small-cell lung carcinoma (NSCLC) cells are relatively TRAIL resistant. Identification of small molecules that can restore NSCLC susceptibility to TRAIL-induced apoptosis is meaningful. We found here that rotenone, as a mitochondrial respiration inhibitor, preferentially increased NSCLC cells sensitivity to TRAIL-mediated apoptosis at subtoxic concentrations, the mechanisms by which were accounted by the upregulation of death receptors and the downregulation of c-FLIP (cellular FLICE-like inhibitory protein). Further analysis revealed that death receptors expression by rotenone was regulated by p53, whereas c-FLIP downregulation was blocked by Bcl-XL overexpression. Rotenone triggered the mitochondria-derived reactive oxygen species (ROS) generation, which subsequently led to Bcl-XL downregulation and PUMA upregulation. As PUMA expression was regulated by p53, the PUMA, Bcl-XL and p53 in rotenone-treated cells form a positive feedback amplification loop to increase the apoptosis sensitivity. Mitochondria-derived ROS, however, promote the formation of this amplification loop. Collectively, we concluded that ROS generation, Bcl-XL and p53-mediated amplification mechanisms had an important role in the sensitization of NSCLC cells to TRAIL-mediated apoptosis by rotenone. The combined TRAIL and rotenone treatment may be appreciated as a useful approach for the therapy of NSCLC that warrants further investigation.

Highlights

(TRAIL) has emerged as a promising cancer therapeutic because it can selectively induce apoptosis in tumor cells in vitro, and most importantly, in vivo with little adverse effect on normal cells.[1]
Ligation of TRAIL to DR4 or DR5 allows for the recruitment of Fas-associated protein with death domain (FADD), which leads to the formation of death-inducing signaling complex (DISC) and the subsequent activation of caspase-8/10.6 The effector caspase-3 is activated by caspase-8, which cleaves numerous regulatory and structural proteins resulting in cell apoptosis
The apoptosis-enhancing effect of rotenone occurred independent of its cytotoxicity, because the minimal dosage required for rotenone to cause toxic effect on non-small-cell lung carcinoma (NSCLC) cell lines was 10 μM, rotenone augmented TRAILmediated apoptosis when it was used as little as 10 nM

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Introduction

(TRAIL) has emerged as a promising cancer therapeutic because it can selectively induce apoptosis in tumor cells in vitro, and most importantly, in vivo with little adverse effect on normal cells.[1]. Rotenone suppresses c-FLIP expression and increases the sensitivity of A549 cells to TRAIL-induced apoptosis.

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