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

• Published in: Cancer letters 2009-05, Vol.277 (2), p.133-140
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Biphenyl Compounds - pharmacology; Breast cancer; Breast Neoplasms; Cell cycle; Cell Cycle - drug effects; Cell Cycle - physiology; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Down-Regulation; Epidermal growth factor; Female; Hematology, Oncology and Palliative Medicine; Honokiol; Humans; Kinases; Lignans - pharmacology; MDA-MB-231; mTOR; Phosphorylation; Protein-Tyrosine Kinases - biosynthesis; Receptor, Epidermal Growth Factor - biosynthesis; Signal Transduction; Src; src-Family Kinases; Tumor Suppressor Proteins - metabolism
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2008.11.029

Abstract 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.