Down-regulation of c-Src/EGFR-mediated signaling activation is involved in the honokiol-induced cell cycle arrest and apoptosis in MDA-MB-231 human breast cancer cells

作者：Park Eun Jung; Min Hye Young; Chung Hwa Jin; Hong Ji Young; Kang You Jin; Hung Tran Manh; Youn Ui Joung; Kim Yeong Shik; Bae KiHwan; Kang Sam Sik; Lee Sang Kook^*

来源：Cancer Letters, 2009, 277(2): 133-140.

DOI：10.1016/j.canlet.2008.11.029

• Honokiol
• MDA-MB-231
• Apoptosis
• Src
• mTOR

Honokiol is a naturally occurring neolignan abundant in Magnoliae Cortex and has showed anti-proliferative and pro-apoptotic effects in a wide range of human cancer cells. However, the molecular mechanisms on the anti-proliferative activity in cancer cells have been poorly elucidated. In this study, we evaluated the growth inhibitory activity of honokiol in cultured estrogen receptor (ER)-negative MDA-MB-231 human breast cancer cells. Honokiol exerted anti-proliferative activity with the cell cycle arrest at the G0/G1 phase and sequential induction of apoptotic cell death in a concentration-dependent manner. The honokiol-induced cell cycle arrest was well correlated with the suppressive expression of CDK4, cyclin D1, CDK2, cyclin E, c-Myc, and phosphorylated retinoblastoma protein (pRb) at Ser780. Apoptosis caused by honokiol was also concomitant with the cleavage of caspases (caspase-3, -8, and -9) and Bid along with the suppressive expression of Bcl-2, but it was independent on the expression of Bax and p53. In addition, honokiol-treated cells exhibited the cleavage of poly (ADP-ribose) polymerase (PARP) and DNA fragmentation. In the analysis of signal transduction pathway, honokiol down-regulated the expression and phosphorylation of c-Src, epidermal growth factor receptor (EGFR), and Akt, and consequently led to the inactivation of mTOR and its downstream signal molecules including 4E-binding protein (4E-BP) and p70 S6 kinase. These findings suggest that honokiol-mediated inhibitory activity of cancer cell growth might be related with the cell cycle arrest and induction of apoptosis via modulating signal transduction pathways.

• 出版日期2009-5-18