14th April 06:58
inhibition of survivin induction by taxol significantly increased taxol-mediated cell death (cancer)
J Biol Chem. 2004 Jan 13 [Epub ahead of print] Related Articles, Links
Induction of survivin expression by taxol (paclitaxel) is an early event
which is independent of taxol-mediated G2/M arrest.
Ling X, Bernacki RJ, Brattain MG, Li F.
Pharmacology and The****utics, Roswell Park Cancer Institute, Buffalo, NY
Survivin is a novel anti-apoptotic protein that is highly expressed in
cancer but is undetectable in most normal adult tissues. It was reported
that taxol-mediated mitotic arrest of cancer cells is associated with
survivin induction, which preserves a survival pathway and results in
resistance to taxol. In this study, we provide new evidence that induction
of survivin by taxol is an early event and is independent of taxol-mediated
G2/M arrest. Taxol treatment of MCF-7 cells rapidly upregulated survivin
expression (3.5-15 fold) within 4 hours without G2/M arrest. Lengthening the
treatment of cells (48 hours) with taxol resulted in decreased survivin
expression in comparison with early times following taxol treatment although
G2/M cells were significantly increased at later times. Interestingly, 3 nM
taxol induces survivin as effectively as 300 nM and more effectively than
3000 nM. As a result, 3nM taxol is ineffective at inducing cell death.
However, inhibition of taxol-mediated survivin induction by small
interfering RNA significantly increased taxol-mediated cell death. Taxol
rapidly activated the PI3K/Akt and MAPK pathways. Inhibition of these
pathways diminished survivin induction and sensitized cells to
taxol-mediated cell death. A cis-acting DNA element upstream of 1430 in the
survivin pLuc-2840 construct is at least partially responsible for
taxol-mediated survivin induction. Together, these data show, for the first
time, that taxol-mediated induction of survivin is an early event and
independent of taxol-mediated G2/M arrest. This appears to be a new
mechanism for cancer cells to evade taxol-induced apoptosis. Targeting this
survival pathway may result in novel approaches for cancer the****utics.