title: Cristacarpin promotes ER stress-mediated ROS generation leading to premature senescence by activation of p21(waf-1).
abstract: 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.
authors.affiliation: Academy of Scientific & Innovative Research (AcSIR), New Delhi, India.|Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K, 180001, India.
authors.forename: Souneek
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Academy of Scientific & Innovative Research (AcSIR), New Delhi, India.|Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K, 180001, India.
authors.forename: Reyaz Ur
authors.initials: RU
authors.lastname: Rasool
authors.affiliation: Natural Product Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K, 180001, India.
authors.forename: Sunil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Academy of Scientific & Innovative Research (AcSIR), New Delhi, India.|Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K, 180001, India.
authors.forename: Debasis
authors.initials: D
authors.lastname: Nayak
authors.affiliation: University of Nebraska Medical Center (UNMC), Omaha, NE, USA.
authors.forename: Bilal
authors.initials: B
authors.lastname: Rah
authors.affiliation: Academy of Scientific & Innovative Research (AcSIR), New Delhi, India.|Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K, 180001, India.
authors.forename: Archana
authors.initials: A
authors.lastname: Katoch
authors.affiliation: Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K, 180001, India.
authors.forename: Hina
authors.initials: H
authors.lastname: Amin
authors.affiliation: Academy of Scientific & Innovative Research (AcSIR), New Delhi, India.|Natural Product Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K, 180001, India.
authors.forename: Asif
authors.initials: A
authors.lastname: Ali
authors.affiliation: Academy of Scientific & Innovative Research (AcSIR), New Delhi, India. agoswami@iiim.ac.in.|Cancer Pharmacology Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi, J&K, 180001, India. agoswami@iiim.ac.in.
authors.forename: Anindya
authors.initials: A
authors.lastname: Goswami
mesh_terms: D000375:Aging / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D018384:Oxidative Stress; D036343:Pterocarpans / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D036343:Pterocarpans; D017382:Reactive Oxygen Species; C085157:cristacarpin
keywords: Cristacarpin; GRP-78; ROS; Senescence; p21waf1; p38MAPK