Abstract
Interferon regulatory factor-4 binding protein (IBP) is a novel upstream activator of Rho GTPases. Our previous studies have shown that ectopic expression of IBP was correlated with malignant behaviors of human breast cancer cells, and invasive human breast cancer had high expression of IBP that promoted the proliferation of these cells. However, it remains unknown whether autophagy inhibition contributes to IBP-mediated tumorigenesis. In this study, we for the first time, reported that upregulation of IBP expression significantly suppressed the autophagy of breast cancer cells, and downregulation of IBP expression markedly induced autophagy of these cells. Further investigation revealed that IBP effectively counteracted autophagy by directly activating mammalian target of rapamycin complex 2 (mTORC2) and upregulating phosphorylation of Akt on ser473 and FOXO3a on Thr32. Moreover, IBP-mediated suppression of autophagy was dependent on mTORC2/Akt/FOXO3a signaling pathway. Finally, our results demonstrated that IBP-mediated breast cancer cell growth in vitro and in vivo was strongly correlated with suppression of mTORC2-dependent autophagy. These findings suggest that the anti-autophagic property of IBP has an important role in IBP-mediated tumorigenesis, and IBP may serve as an attractive target for treatment of breast cancer.
Highlights
Interferon regulatory factor binding protein (IBP) was first identified in 20033 and has been found to have multiple roles in the biological processes of the immune system
light chain 3 (LC3)-I is converted to lipidated LC3-II, which is the classical hallmarks of autophagy.[25,26] p62 protein is a well-known autophagic substrate.[27,28]
We report for the first time that IBP inhibits autophagy of breast cancer cells
Summary
Interferon regulatory factor binding protein (IBP) was first identified in 20033 and has been found to have multiple roles in the biological processes of the immune system. The phosphorylation in Thr[32] of FOXO3a results in translocation of FOXO from the nucleus, which inhibits the transcription of autophagy-related genes.[23,24] Importantly, Akt activation of Ser[473], a downstream target of mTORC2, promotes the FoxO3 phosphorylation, and autophagy is suppressed . This effect is not prevented by rapamycin (a mTORC1 inhibitor). Our in vitro and in vivo findings revealed that OSI-027 (a mTORC2/mTORC1 inhibitor) reversed the IBP-mediated autophagy inhibition, and obviously blocked the IBP-mediated activation of the mTORC2/Akt/FOXO3a signaling pathway, and inhibited the IBP-induced cell growth and metastasis of breast cancer cells. Our study for the first time indicates that the antiautophagic property of IBP has a key role in the IBP-mediated tumorigenesis, and may, to some extent, serve as an attractive target for breast cancer therapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
