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

• Published in: Frontiers in oncology Vol. 12; p. 1013500
• Main Authors: Mir, Khalid Bashir, Faheem, Mir Mohd, Ahmad, Syed Mudabir, Rasool, Javeed Ur, Amin, Tanzeeba, Chakraborty, Souneek, Bhagat, Madhulika, Ahmed, Zabeer, Ali, Asif, Goswami, Anindya
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 17.11.2022
• Subjects: arteannuin B; ATF-4; autophagy; breast cancer; C/EBPβ; Oncology; senescence; C/EBPβ; senescence; ATF-4; arteannuin B; breast cancer; autophagy
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2022.1013500

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 -(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 G /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 .