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Inhibition of JNK-Mediated Autophagy Promotes Proscillaridin A- Induced Apoptosis via ROS Generation, Intracellular Ca +2 Oscillation and Inhibiting STAT3 Signaling in Breast Cancer Cells

  • Saleem, Muhammad Zubair1
  • Alshwmi, Mohammed2
  • Zhang, He1
  • Din, Syed Riaz Ud1
  • Nisar, Muhammad Azhar1
  • Khan, Muhammad3
  • Alam, Shahid4
  • Alam, Gulzar5
  • Jin, Lingling1
  • Ma, Tonghui1, 6
  • 1 College of Basic Medical Sciences, Dalian Medical University, Dalian , (China)
  • 2 Department of Clinical Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian , (China)
  • 3 Department of Zoology, University of the Punjab, Lahore , (Pakistan)
  • 4 Department of Anatomy, Dalian Medical University, Dalian , (China)
  • 5 Advanced Institute for Medical Sciences, Dalian Medical University, Dalian , (China)
  • 6 School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing , (China)
Published Article
Frontiers in Pharmacology
Frontiers Media SA
Publication Date
Sep 04, 2020
DOI: 10.3389/fphar.2020.01055
PMID: 33013353
PMCID: PMC7500466
PubMed Central


Breast cancer is the most heterogenous cancer type among women across the world. Despite concerted efforts, breast cancer management is still unsatisfactory. Interplay between apoptosis and autophagy is an imperative factor in categorizing therapeutics for cancer treatment. Proscillaridin A (PSD-A), a well-known cardiac glycoside used for cardiac arrest and arrythmias, has been unveiled in many cancer types but the underlying mechanism for apoptosis and autophagy in breast cancer is not fully understood. In our study, PSD-A restricted cell growth, inhibited STAT3 activation and induced apoptosis and autophagy in breast cancer cells via ROS generation and Ca+2 oscillation. Pretreatment of NAC and BAPTA-AM restored PSD-A induced cellular events in breast cancer cells. PSD-A induced apoptosis via DNA fragmentation, caspase-cascade activation, PARP cleavage, mitochondrial dysfunction, Bax/Bcl-2 proteins modulation and ER chaperone GRP78 inhibition along with decreased phosphorylation of ERK1/2. Inhibition of STAT3 activation was found to be associated with decreased phosphorylation of SRC. Moreover, PSD-A induced events of autophagy i.e. conversion of LC3-I to LC3-II, and Atg3 expression via JNK activation and decreased mTOR and AKT phosphorylation. In this study, pretreatment of SP600125, a JNK inhibitor, reduced autophagy and enhanced STAT3 inhibition and apoptosis. Additionally, SB203580, a commercial p38 inhibitor, stimulated STAT3 activation and improved autophagic events rate in breast cancer cells, displaying the role of the MAPK signaling pathway in interplay between apoptosis and autophagy. Our data suggest that the rate of apoptotic cell death is improved by blocking JNK-induced autophagy in PSD-A treated MCF-7 and MDA-MB-231 breast cancer cells.

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