We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Flavagline analog FL3 induces cell cycle arrest in urothelial carcinoma cell of the bladder by inhibiting the Akt/PHB interaction to activate the GADD45α pathway.
- Authors
Gangjun Yuan; Xin Chen; Zhuowei Liu; Wensu Wei; Qinghai Shu; Abou-Hamdan, Hussein; Lijuan Jiang; Xiangdong Li; Rixin Chen; Laurent Désaubry; Fangjian Zhou; Dan Xie
- Abstract
Background: Prohibitin 1 (PHB) is a potential target for the treatment of urothelial carcinoma of the bladder (UCB). FL3 is a newly synthesized agent that inhibits cancer cell proliferation by targeting the PHB protein; however, the effect of FL3 in UCB cells remains unexplored. Methods: FL3 was identified to be a potent inhibitor of UCB cell viability using CCK-8 (cell counting kit-8) assay. Then a series of in vitro and in vivo experiments were conducted to further demonstrate the inhibitory effect of FL3 on UCB cell proliferation and to determine the underlying mechanisms. Results: FL3 inhibited UCB cell proliferation and growth both in vitro and in vivo. By targeting the PHB protein, FL3 inhibited the interaction of Akt and PHB as well as Akt-mediated PHB phosphorylation, which consequently decreases the localization of PHB in the mitochondria. In addition, FL3 treatment resulted in cell cycle arrest in the G2/M phase, and this inhibitory effect of FL3 could be mimicked by knockdown of PHB. Through the microarray analysis of mRNA expression after FL3 treatment and knockdown of PHB, we found that the mRNA expression of the growth arrest and DNA damage-inducible alpha (GADD45α) gene were significantly upregulated. When knocked down the expression of GADD45α, the inhibitory effect of FL3 on cell cycle was rescued, suggesting that FL3-induced cell cycle inhibition is GADD45a dependent. Conclusion: Our data provide that FL3 inhibits the interaction of Akt and PHB, which in turn activates the GADD45α-dependent cell cycle inhibition in the G2/M phase.
- Subjects
TRANSITIONAL cell carcinoma; BLADDER cancer; CELL cycle; POLY-beta-hydroxybutyrate; MESSENGER RNA; DNA damage
- Publication
Journal of Experimental & Clinical Cancer Research (17569966), 2018, Vol 37, p1
- ISSN
1756-9966
- Publication type
Article
- DOI
10.1186/s13046-018-0695-5