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J. Biol. Chem., Vol. 277, Issue 36, 33490-33500, September 6, 2002
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From the Department of Obstetrics and Gynecology, Osaka University
Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
We studied the roles of the
phosphatidylinositol 3-kinase (PI-3K)-Akt-BAD cascade, ERK-BAD cascade,
and Akt-Raf-1 cascade in the paclitaxel-resistant SW626 human ovarian
cancer cell line, which lacks functional p53. Treatment of SW626 cells
with paclitaxel activates Akt and ERK with different time frames.
Interference with the Akt cascade either by treatment with PI-3K
inhibitor (wortmannin or LY294002) or by exogenous expression of a
dominant negative Akt in SW626 cells caused decreased cell viability
following treatment with paclitaxel. Interference with the ERK cascade
by treatment with an MEK inhibitor, PD98059, in SW626 cells also caused
decreased cell viability following treatment with paclitaxel. Treatment
of cells with paclitaxel also stimulated the phosphorylation of BAD at
both the Ser-112 and Ser-136 sites. The phosphorylation of BAD at
Ser-136 was blocked by treatment with wortmannin or cotransfection with
the dominant negative Akt. On the other hand, the phosphorylation of
BAD at Ser-112 was blocked by PD98059. We further examined the role of
BAD in the viability following paclitaxel treatment using BAD
mutants. Exogenous expression of doubly substituted BAD2SA in SW626
cells caused decreased viability following treatment with paclitaxel.
Moreover, because paclitaxel-induced apoptosis is mediated by activated
Raf-1 and the region surrounding Ser-259 in Raf-1 conforms to a
consensus sequence for phosphorylation by Akt, the regulation of Raf-1
by Akt was examined. We demonstrated an association between Akt and
Raf-1 and showed that the phosphorylation of Raf-1 on Ser-259 induced
by paclitaxel was blocked by treatment with wortmannin or LY294002.
Furthermore, interference with the Akt cascade induced by paclitaxel
up-regulated Raf-1 activity, and expression of constitutively active
Akt inhibited Raf-1 activity, suggesting that Akt negatively regulates
Raf-1. Our findings suggest that paclitaxel induces the phosphorylation
of BAD Ser-112 via the ERK cascade, and the phosphorylation of both BAD
Ser-136 and Raf-1 Ser-259 via the PI-3K-Akt cascade, and that
inhibition of either of these cascades sensitizes ovarian cancer cells
to paclitaxel.
Inhibition of Phosphorylation of BAD and Raf-1 by Akt Sensitizes
Human Ovarian Cancer Cells to Paclitaxel*
,
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence and reprint requests should be addressed:
Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.: 11-81-6-6879-3354; Fax: 11-81-6-6879-3359; E-mail:
masa@gyne.med.osaka-u.ac.jp.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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