On the role of different signal transduction pathways in induction of apoptosis by anticancer drugs
Author: Berndtsson, Maria
Date: 2007-05-04
Location: Radiumhemmets föreläsningssal, Karolinska Universitetssjukhuset
Time: 10.00
Department: Institutionen för onkologi-patologi / Department of Oncology-Pathology
View/ Open:
thesis.pdf (1.500Mb)
Abstract
Anticancer drug treatment gives rise to complex cellular responses in
tumor cells. An improved understanding of the mechanisms underlying these
responses is important in order to improve treatment. It is also of
importance to investigate novel mechanisms of drug action that could
potentially represent new concepts for treatment. In this thesis, both
clinically used anticancer agents as well as other agents inducing tumor
cell death were studied.
The DNA damaging agents cisplatin and ellipticine were shown to also
exert non-nuclear effects important for apoptotic signaling such as
induction of endoplasmic reticulum stress and for cisplatin also
generation of reactive oxygen species. Cisplatin was shown to trigger
distinct cellular outcomes depending on the concentration used. Our data
suggest that DNA damage signaling primarily induces senescence. Acute
apoptosis is mostly independent of DNA damage responses and is rather
triggered by cytoplasmic events such as generation of reactive oxygen
species.
A chemical library was screened for compounds inducing apoptosis
independently of p53. It was found that lysosomes often are involved in
p53-independent apoptotic signaling. Lysosomal apoptosis signaling was
further examined by screening for compounds that induce
cathepsin-dependent apoptosis. Among the most potent agents identified
were two compounds with similar chemical structures that were found to
induce the accumulation of polyubiquitins in cells. Our data raise the
possibility that inhibition of the ubiquitin-proteasomal system may lead
to the triggering of lysosomal membrane permeabilization.
Apoptosis induction by the anticancer agent paclitaxel was examined with
a focus on the potential involvement of the proapoptotic protein Bad. We
found Bad to be phosphorylated at Ser 128, a site reported to enhance its
proapoptotic activity, after paclitaxel treatment. Our data does not
however suggest an important role for this phosphorylation event in
paclitaxel-induced apoptosis.
The studies in this thesis illustrate the complexity of cellular
responses triggered by anticancer drugs. The signaling pathways often
involve different cellular organelles and the outcome of treatment can
include various forms of antiproliferative responses.
List of papers:
I. Berndtsson M, Konishi Y, Bonni A, Hagg M, Shoshan M, Linder S, Havelka AM (2005). "Phosphorylation of BAD at Ser-128 during mitosis and paclitaxel-induced apoptosis." FEBS Lett 579(14): 3090-4
Pubmed
II. Hagg M, Berndtsson M, Mandic A, Zhou R, Shoshan MC, Linder S (2004). "Induction of endoplasmic reticulum stress by ellipticine plant alkaloids." Mol Cancer Ther 3(4): 489-97
Pubmed
III. Berndtsson M, Hagg M, Panaretakis T, Havelka AM, Shoshan MC, Linder S (2007). "Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA." Int J Cancer 120(1): 175-80
Pubmed
IV. Erdal H, Berndtsson M, Castro J, Brunk U, Shoshan MC, Linder S (2005). "Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis." Proc Natl Acad Sci U S A 102(1): 192-7. Epub 2004 Dec 23
Pubmed
V. Berndtsson M, Beaujouin M, Mandic Havelka A, Larsson R, Westman J, Liaudet-Coopman E, Linder S (2007). "Induction of cathepsin-dependent apoptosis by inhibitors of the ubiquitin-proteasome system." (Manuscript)
I. Berndtsson M, Konishi Y, Bonni A, Hagg M, Shoshan M, Linder S, Havelka AM (2005). "Phosphorylation of BAD at Ser-128 during mitosis and paclitaxel-induced apoptosis." FEBS Lett 579(14): 3090-4
Pubmed
II. Hagg M, Berndtsson M, Mandic A, Zhou R, Shoshan MC, Linder S (2004). "Induction of endoplasmic reticulum stress by ellipticine plant alkaloids." Mol Cancer Ther 3(4): 489-97
Pubmed
III. Berndtsson M, Hagg M, Panaretakis T, Havelka AM, Shoshan MC, Linder S (2007). "Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA." Int J Cancer 120(1): 175-80
Pubmed
IV. Erdal H, Berndtsson M, Castro J, Brunk U, Shoshan MC, Linder S (2005). "Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis." Proc Natl Acad Sci U S A 102(1): 192-7. Epub 2004 Dec 23
Pubmed
V. Berndtsson M, Beaujouin M, Mandic Havelka A, Larsson R, Westman J, Liaudet-Coopman E, Linder S (2007). "Induction of cathepsin-dependent apoptosis by inhibitors of the ubiquitin-proteasome system." (Manuscript)
Issue date: 2007-04-13
Rights:
Publication year: 2007
ISBN: 978-91-7357-176-0
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