Cristacarpin promotes ER stress-mediated ROS generation leading to premature senescence by activation of p21(waf-1).

Authors:
MR Souneek Chakraborty
MR Souneek Chakraborty
Indian Institute of Integrative Medicine (CSIR)
Cancer Pharmacology
Cancer metastasis, EMT, apoptosis, senescence
kolkata, west bengal | India
Reyaz Ur Rasool
Reyaz Ur Rasool
CSIR-Indian Institute of Integrative Medicine
Dr. Sunil Kumar, DM (Neurology)
Dr. Sunil Kumar, DM (Neurology)
Shri Ram Murti Smarak Institute of Medical Sciences, Bareilly
Neurologist
Neurology
Bareilly, Uttar Pradesh | India
Debasis Nayak
Debasis Nayak
Immunology and Molecular Medicine Laboratory
Redwood City | United States
Bilal Rah
Bilal Rah
Apoptosis/Autophagy/Anti-cancer drug discovery
Archana Katoch
Archana Katoch
CSIR-Indian Institute of Integrative Medicine
Hina Amin
Hina Amin
CSIR-Indian Institute of Integrative Medicine
India
Mr Asif Ali, PhD
Mr Asif Ali, PhD
Sichuan Agricultural University,
Plant Breeding and Genetics
Wenjigang, Sichuan | China

Age (Dordr) 2016 Jun 31;38(3):62. Epub 2016 May 31.

Academy of Scientific & Innovative Research (AcSIR), New Delhi, India.

Stress-induced premature senescence (SIPS) is quite similar to replicative senescence that is committed by cells exposed to various stress conditions viz. ultraviolet radiation (DNA damage), hydrogen peroxide (oxidative stress), chemotherapeutic agents (cytotoxic threat), etc. Here, we report that cristacarpin, a natural product obtained from the stem bark of Erythrina suberosa, promotes endoplasmic reticulum (ER) stress, leading to sub-lethal reactive oxygen species (ROS) generation and which eventually terminates by triggering senescence in pancreatic and breast cancer cells through blocking the cell cycle in the G1 phase. The majority of cristacarpin-treated cells responded to conventional SA-β-gal stains; showed characteristic p21(waf1) upregulation along with enlarged and flattened morphology; and increased volume, granularity, and formation of heterochromatin foci-all of these features are the hallmarks of senescence. Inhibition of ROS generation by N-acetyl-L-cysteine (NAC) significantly reduced the expression of p21(waf1), confirming that the modulation in p21(waf1) by anti-proliferative cristacarpin was ROS dependent. Further, the elevation in p21(waf1) expression in PANC-1 and MCF-7 cells was consistent with the decrease in the expression of Cdk-2 and cyclinD1. Here, we provide evidence that cristacarpin promotes senescence in a p53-independent manner. Moreover, cristacarpin treatment induced p38MAPK, indicating the ROS-dependent activation of the MAP kinase pathway, and thus abrogates the tumor growth in mouse allograft tumor model.

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http://dx.doi.org/10.1007/s11357-016-9922-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005927PMC

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June 2016
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