Table of Contents Author Guidelines Submit a Manuscript
Oxidative Medicine and Cellular Longevity
Volume 2018, Article ID 3853409, 17 pages
https://doi.org/10.1155/2018/3853409
Research Article

Proscillaridin A Promotes Oxidative Stress and ER Stress, Inhibits STAT3 Activation, and Induces Apoptosis in A549 Lung Adenocarcinoma Cells

1College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning 116044, China
2Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, Liaoning 116044, China

Correspondence should be addressed to Muhammad Khan; moc.liamy@tsigolooz_nahk and Tonghui Ma; nc.ude.udemld@amiuhgnot

Received 26 July 2017; Revised 21 October 2017; Accepted 16 November 2017; Published 11 January 2018

Academic Editor: Javier Egea

Copyright © 2018 Amara Maryam et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Cardiac glycosides are natural compounds used for the treatment of cardiovascular disorders. Although originally prescribed for cardiovascular diseases, more recently, they have been rediscovered for their potential use in the treatment of cancer. Proscillaridin A (PSD-A), a cardiac glycoside component of Urginea maritima, has been reported to exhibit anticancer activity. However, the cellular targets and anticancer mechanism of PSD-A in various cancers including lung cancer remain largely unexplored. In the present study, we found that PSD-A inhibits growth and induces apoptosis in A549 lung adenocarcinoma cells. The anticancer activity of PSD-A was found to be associated with the activation of JNK, induction of ER stress, mitochondrial dysfunction, and inhibition of STAT3 activation. PSD-A induces oxidative stress as evidenced from ROS generation, GSH depletion, and decreased activity of TrxR1. PSD-A-mediated ER stress was verified by increased phosphorylation of eIF2α and expression of its downstream effector proteins ATF4, CHOP, and caspases-4. PSD-A triggered apoptosis by inducing JNK (1/2) activation, increasing bax/bcl-2 ratio, dissipating mitochondrial membrane potential, and inducing cleavage of caspases and PARP. Further study revealed that PSD-A inhibits both constitutive and inducible STAT3 activations and decreases STAT3 DNA-binding activity. Moreover, PSD-A-mediated inhibition of STAT3 activation was found to be associated with increased SHP-1 expression, decreased phosphorylation of Src, and binding of PSD-A with STAT3 SH2 domain. Finally, STAT3 knockdown by shRNA inhibited growth and enhanced apoptotic efficacy of PSD-A. Taken together, the data suggest that PSD-A could be developed into a potential therapeutic agent against lung adenocarcinoma.