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

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.

Scutellarin suppresses proliferation and promotes apoptosis in A549 lung adenocarcinoma cells via AKT/mTOR/4EBP1 and STAT3 pathways

“…STAT3, a member of the STAT family, is involved in oncogenic transformation and progression in some cancer types, including lung cancer . The antiapoptotic protein, BCL‐XL, is a key protein downstream of the STAT3 signaling pathway .…”

“…STAT3, a member of the STAT family, is involved in oncogenic transformation and progression in some cancer types, including lung cancer. 11,12 The antiapoptotic protein, BCL-XL, is a key protein downstream of the STAT3 signaling pathway. 18 In the current study, we found that t-STAT3, p-STAT3, and BCL-XL were significantly decreased in A549 cells treated with SCU in concentration-dependent manners.…”

“…STAT3 is recognized as a key target in the progression of various malignancies . Aberrantly active STAT3 promotes tumorigenesis, drug resistance, and metastasis in NSCLC . Downstream signaling effects of the STAT3 pathway can contribute to lung cancer and currently several STAT3 inhibitors show substantial anticancer and antiangiogenic effects .…”

“…11 Aberrantly active STAT3 promotes tumorigenesis, drug resistance, and metastasis in NSCLC. 12 Downstream signaling effects of the STAT3 pathway can contribute to lung cancer and currently several STAT3 inhibitors show substantial anticancer and antiangiogenic effects. 13,14 Finding novel agents with STAT3 suppressive activity is vitally important to improve NSCLC treatment.…”

<p>Brevilin A Inhibits STAT3 Signaling and Induces ROS-Dependent Apoptosis, Mitochondrial Stress and Endoplasmic Reticulum Stress in MCF-7 Breast Cancer Cells</p>

“…Among these, c-Jun N-terminal kinase (JNK) and p38 are prominent members involved in apoptosis. 28,29 In previous studies, it has been demonstrated that high level of ROS generation in cells induces apoptosis via JNK pathway. 8 In our study, Brv-A increased phosphorylation of JNK and p38 without affecting total JNK and p38 ( Figure 5A and B).…”