MHY-449, a novel dihydrobenzofuro[4,5-b][1,8] naphthyridin-6-one derivative, induces apoptotic cell death through modulation of Akt/FoxO1 and ERK signaling in PC3 human prostate cancer cells

Lee,Sun Hwa; Kang,Yong Jung; Sung,Bokyung; Kim,Dong Hwan; Lim,Hyun Sook; Kim,Hye Rim; Kim,Seong Jin; Yoon,Jeong-Hyun; Moon,Hyung Ryong; Chung,Hae Young; Kim,Nam Deuk

doi:10.3892/ijo.2014.2257

MHY-449, a novel dihydrobenzofuro[4,5-b][1,8] naphthyridin-6-one derivative, induces apoptotic cell death through modulation of Akt/FoxO1 and ERK signaling in PC3 human prostate cancer cells

Authors:
- Sun Hwa Lee
- Yong Jung Kang
- Bokyung Sung
- Dong Hwan Kim
- Hyun Sook Lim
- Hye Rim Kim
- Seong Jin Kim
- Jeong-Hyun Yoon
- Hyung Ryong Moon
- Hae Young Chung
- Nam Deuk Kim
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Affiliations: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea
Published online on: January 10, 2014 https://doi.org/10.3892/ijo.2014.2257
Pages: 905-911

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Abstract

Previously, we reported on the anticancer effect of the diastereoisomeric compound MHY-449, a novel dihydrobenzofuro[4,5-b][1,8] naphthyridin-6-one derivative, in HCT116 human colon cancer cells. In the current study, we investigated whether MHY-449 has anticancer effect in prostate cancer cells, and if so, what the molecular mechanisms are. We examined the growth inhibitory effect of MHY-449 on p53 wild‑type (p53-wt) LNCaP (androgen‑dependent) and p53-null PC3 (androgen-independent) prostate cancer cells. MHY-449 treatment in androgen-independent and p53-null PC3 cells resulted in inhibition of cell growth and induction of apoptosis in a concentration-dependent manner. However, MHY-449 did not show any significant effects on the growth inhibition and apoptotic cell death in androgen-dependent and p53-wt LNCaP cells. Therefore, we used PC3 cells for further studies. The induction of apoptosis in PC3 cells was observed by decreased viability, DNA fragmentation, cleavage of poly (ADP-ribose) polymerase, activations of caspase-3, -8 and -9, and alteration in the ratio of Bax/Bcl-2 protein expression. In addition, MHY-449 induced increase of late apoptosis and sub-G1 DNA which were observed by flow cytometry analysis. Furthermore, MHY-449 reduced the phosphorylation of Akt and FoxO1 and induced the translocation of FoxO1 from cytoplasm to nucleus as shown by western blot analysis. MHY-449 treatment activated extracellular signal-regulated kinase (ERK) signaling in a concentration-dependent manner. MHY-449-induced apoptosis was partially prevented by pretreatment with the ERK inhibitor PD98059 suggesting involvement of ERK in the MHY-449-induced apoptosis. Taken together, these findings suggest that MHY-449 induces apoptosis via downregulation of the Akt/FoxO1 and activation of ERK in androgen-independent, p53-null and PTEN-negative PC3 human prostate cancer cells.

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