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

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 beta-(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(2)/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/EBP beta. 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/EBP beta 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.

Automated summary

ATF-4 serves as a crucial regulator in cellular stress response, directing cells towards autophagy or apoptosis/senescence pathways. Arteannuin 09, by activating ATF-4, induces autophagy and subsequently leads to G(2)/M cell cycle arrest through upregulation of p21. The interaction between ATF-4 and C/EBP beta is essential for cell cycle regulation and inhibition of autophagy signaling can switch the fate of cells from senescence to apoptosis under Arteannuin 09 treatment.