Long-term Forskolin Stimulation Induces AMPK Activation and Thereby Enhances Tight Junction Formation in Human Placental Trophoblast BeWo Cells

Egawa, M.; Kamata, H.; Kushiyama, A.; Sakoda, H.; Fujishiro, M.; Horike, N.; Yoneda, M.; Nakatsu, Y.; Ying, Guo; Jun, Zhang; Tsuchiya, Y.; Takata, K.; Kurihara, H.; Asano, T.

doi:10.1016/j.placenta.2008.09.008

« Previous Next »Placenta
Volume 29, Issue 12 , Pages 1003-1008, December 2008

Long-term Forskolin Stimulation Induces AMPK Activation and Thereby Enhances Tight Junction Formation in Human Placental Trophoblast BeWo Cells

M. Egawa
- Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8551, Japan
H. Kamata
- Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8551, Japan
A. Kushiyama
- The Institute for Adult Diseases, Asahi Life Foundation, 1-6-1 Marunouchi, Tiyoda-ku, Tokyo 100-0005, Japan
H. Sakoda
- Department of Internal Medicine, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
M. Fujishiro
- Department of Internal Medicine, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
N. Horike
- Department of Physiological Chemistry and Metabolism, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
M. Yoneda
- Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8551, Japan
Y. Nakatsu
- Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8551, Japan
Guo Ying
- Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8551, Japan
Zhang Jun
- Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8551, Japan
Y. Tsuchiya
- Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8551, Japan
K. Takata
- Department of Cell Biology, Institute for Cellular and Molecular Regulation, Gunma University, 3-39-15 Showamachi, Maebashi, Gunma 371-8512, Japan
H. Kurihara
- Department of Physiological Chemistry and Metabolism, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
T. Asano
- Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8551, Japan
- Corresponding author. Tel.: +81 82 257 5135; fax: +81 82 257 5136.

Accepted 10 September 2008. published online 24 October 2008.

Abstract

BeWo cells, derived from human choriocarcinoma, have been known to respond to forskolin or cAMP analogues by differentiating into multinucleated cells- like syncytiotrophoblasts on the surfaces of chorionic villi of the human placenta. In this study, we demonstrated that long-term treatment with forskolin enhances the tight junction (TJ) formation in human placental BeWo cells. Interestingly, AMPK activation and phosphorylation of acetyl-CoA carboxylase (ACC), a molecule downstream from AMPK, were induced by long-term incubation (>12h) with forskolin, despite not being induced by acute stimulation with forskolin. In addition, co-incubation with an AMPK inhibitor, compound C, as well as overexpression of an AMPK dominant negative mutant inhibited forskolin-induced TJ formation. Thus, although the molecular mechanism underlying AMPK activation via the forskolin stimulation is unclear, the TJ formation induced by forskolin is likely to be mediated by the AMPK pathway. Taking into consideration that TJs are present in the normal human placenta, this mechanism may be important for forming the placental barrier system between the fetal and maternal circulations.