Resveratrol sensitizes lung cancer cell to TRAIL by p53 independent and suppression of Akt/NF-κB signaling

Mohammad Rasheduzzaman,Jae-Kyo Jeong,Sang-Youel Park

doi:10.1016/j.lfs.2018.07.035

Mohammad Rasheduzzaman, Jae-Kyo Jeong + Show 1 more

Open Access

https://doi.org/10.1016/j.lfs.2018.07.035

Copy DOI

Abstract

AimsTRAIL is a promising anticancer agent that has the potential to sensitize a wide variety of cancer or transformed cells by inducing apoptosis. However, resistance to TRAIL is a growing concern. Current manuscript aimed to employ combination treatment to investigate resveratrol induced TRAIL sensitization in NSCLC. MethodA549 and HCC-15 cells were used in an experimental design. Cell viability was determined by morphological image, crystal violet staining and MTT assay. Apoptosis was evaluated by LDH assay, Annexin V and DAPI staining. Autophagy and apoptosis indicator protein were examined by western blotting. TEM and puncta assay was carried out to evaluate the autophagy. MTP and ROS activity was evaluated by JC-1 and H2DCFDA staining. FindingsResveratrol is a polyphenolic compound capable of activation of tumor suppressor p53 and its pro-apoptotic modulator PUMA. Herein, we showed the p53-independent apoptosis by decrease the expression of phosphorylated Akt-mediated suppression of NF-κB that is also substantiated with the downregulation of anti-apoptotic factors Bcl-2 and Bcl-xl in NSCLC, resulting in an attenuation of TRAIL resistance in combined treatment. Furthermore, apoptosis was induced in TRAIL-resistant lung cancer cells with a co-treatment of resveratrol and TRAIL assessed by the loss of MMP, ROS generations which resulting the translocation of cytochrome c from the mitochondria into the cytosol due to mitochondrial dysfunction. Moreover, autophagy flux was not affected by resveratrol-induced TRAIL-mediated apoptosis in NSCLC. SignificanceOverall, targeting the NF-κB (p65) pathway via resveratrol attenuates TRAIL resistance and induces TRAIL-mediated apoptosis which could be the effective TRAIL-based cancer therapy regimen.

Highlights

Cancer is a concerning disease and a leading cause of death
Resveratrol annex the outpouring of p53 & its pro apoptotic modulator PUMA, Here, we demonstrate that p53-independent activation of apoptosis by decrease the expression of phosphorylated Akt -mediated suppression of NF-κB activation results in the downregulation of Bcl-2, Bcl-xl and release of cytochrome c due to mitochondrial dysfunction in A549 human lung adenocarcinoma cells, attenuating Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance
We conclude that a combination treatment using resveratrol and TRAIL is effective against TRAILresistant lung cancer cells via targeting suppression of NF-κB (p65) activity which potentiate mitochondrial dysfunction and apoptosis

Summary

Introduction

Cancer is a concerning disease and a leading cause of death. There are ongoing basic research studies and clinical trials for the developing of treatment options to ameliorate cancer [1]. Studies have shown that numerous anticancer drugs may damage the mitochondria, affecting the mitochondrial membrane potential (MMP), resulting in the release of cytochrome c and subsequent activation of apoptosis via the caspase cascade [21, 22]. NF-κB (p65) regulates anti-apoptotic doi:10.20944/preprints201804.0082.v1 proteins Bcl-2 and Bcl-xl, both of which localize to the mitochondrial outer membrane where they play a significant role in promoting cellular survival and inhibiting pro-apoptotic proteins such as Bax and Bak, which are known to induce apoptosis via permeabilization and the release of cytochrome c [15, 30]. The molecular mechanisms that govern its anticancer activity are still unclear, but it is hypothesized to be associated with cell-cycle arrest and the induction of apoptosis by doi:10.20944/preprints201804.0082.v1 regulating the expression of NF-κB, Bcl-2, and Bcl-xl, or through the loss of mitochondrial function and the release of cytochrome c [49, 50]. In cases of cancer cells that are resistant to TRAIL, a combination therapy of resveratrol with TRAIL can exert potential benefits by attenuating its resistance to TRAIL and enhancing the activation of apoptosis [53,54,55]

Objectives

Methods

Results

Conclusion