β-(4-fluorobenzyl) Arteannuin B induced interaction of ATF-4 and C/EBPβ mediates the transition of breast cancer cells from autophagy to senescence.

Abstract

ATF-4 is a master regulator of transcription of genes essential for cellular-adaptive function. In response to the quantum and duration of stress, ATF-4 diligently responds to both pro-apoptotic and pro-survival signals converging into either autophagy or apoptosis/senescence. Despite emerging cues implying a relationship between autophagy and senescence, how these two processes are controlled remains unknown. Herein, we demonstrate β-(4-fluorobenzyl) Arteannuin B (here after Arteannuin 09), a novel semisynthetic derivative of Arteannuin B, as a potent ER stress inducer leading to the consistent activation of ATF-4. Persistent ATF-4 expression at early time-points facilitates the autophagy program and consequently by upregulating p21 at later time-points, the signaling is shifted towards G2/M cell cycle arrest. As bZIP transcription factors including ATF-4 are obligate dimers, and because ATF-4 homodimers are not highly stable, we hypothesized that ATF-4 may induce p21 expression by physically interacting with another bZIP family member i.e., C/EBPβ. Our co-immunoprecipitation and co-localization studies demonstrated that ATF-4 is principally responsible for the autophagic potential of Arteannuin 09, while as, induction of both ATF-4 and C/EBPβ is indispensable for the p21 regulated-cell cycle arrest. Interestingly, inhibition of autophagy signaling switches the fate of Arteannuin 09 treated cells from senescence to apoptosis. Lastly, our data accomplished that Arteannuin 09 is a potent inhibitor of tumor growth and inducer of premature senescence in vivo.

• Authors: Khalid Bashir Mir, Mir Mohd Faheem, Syed Mudabir Ahmad, Javeed Ur Rasool, Tanzeeba Amin, Souneek Chakraborty, Madhulika Bhagat, Zabeer Ahmed, Asif Ali, Anindya Goswami
• Journal: Frontiers in oncology (Front Oncol) Vol. 12 Pg. 1013500 ( 2022) ISSN: 2234-943X [Print] Switzerland
• PMID: 36465376 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Mir, Faheem, Ahmad, Rasool, Amin, Chakraborty, Bhagat, Ahmed, Ali and Goswami.