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.
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.
Park
Eun-Jung
EJ
College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul, Republic of Korea.
Min
Hye-Young
HY
Chung
Hwa-Jin
HJ
Hong
Ji-Young
JY
Kang
You-Jin
YJ
Hung
Tran Manh
TM
Youn
Ui Joung
UJ
Kim
Yeong Shik
YS
Bae
Kihwan
K
Kang
Sam Sik
SS
Lee
Sang Kook
SK
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001943:Breast Neoplasms; D000081247:CSK Tyrosine-Protein Kinase; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D066246:ErbB Receptors / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D019061:src-Family Kinases; D000498:Allyl Compounds; D010636:Phenols
D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D000081247:CSK Tyrosine-Protein Kinase; D018797:Cell Cycle Proteins; D066246:ErbB Receptors; D017705:Lignans; D011505:Protein-Tyrosine Kinases; D025521:Tumor Suppressor Proteins; D019061:src-Family Kinases; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C512478:EGFR protein, human; C000631346:CSK protein, human