Honokiol suppresses survival signals mediated by Ras-dependent phospholipase D activity in human cancer cells.
OBJECTIVE
Elevated phospholipase D (PLD) activity provides a survival signal in several human cancer cell lines and suppresses apoptosis when cells are subjected to the stress of serum withdrawal. Thus, targeting PLD survival signals has potential to suppress survival in cancer cells that depend on PLD for survival. Honokiol is a compound that suppresses tumor growth in mouse models. The purpose of this study was to investigate the effect of honokiol on PLD survival signals and the Ras dependence of these signals.


METHODS
The effect of honokiol upon PLD activity was examined in human cancer cell lines where PLD activity provides a survival signal. The dependence of PLD survival signals on Ras was investigated, as was the effect of honokiol on Ras activation.


RESULTS
We report here that honokiol suppresses PLD activity in human cancer cells where PLD has been shown to suppress apoptosis. PLD activity is commonly elevated in response to the stress of serum withdrawal, and, importantly, the stress-induced increase in PLD activity is selectively suppressed by honokiol. The stress-induced increase in PLD activity was accompanied by increased Ras activation, and the stress-induced increase in PLD activity in MDA-MB-231 breast cancer cells was dependent on a Ras. The PLD activity was also dependent on the GTPases RalA and ADP ribosylation factor. Importantly, honokiol suppressed Ras activation.


CONCLUSIONS
The data provided here indicate that honokiol may be a valuable therapeutic reagent for targeting a large number of human cancers that depend on Ras and PLD for their survival.
Garcia
Avalon
A
Department of Biological Sciences, Hunter College of The City University of New York, New York 10021, USA.
Zheng
Yang
Y
Zhao
Chen
C
Toschi
Alfredo
A
Fan
Judy
J
Shraibman
Natalie
N
Brown
H Alex
HA
Bar-Sagi
Dafna
D
Foster
David A
DA
Arbiser
Jack L
JL
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004789:Enzyme Activation; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D051379:Mice; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D010739:Phospholipase D / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*; D000498:Allyl Compounds; D010636:Phenols
D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D017705:Lignans; D010739:Phospholipase D; D018631:ras Proteins; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols