On the pro-apoptotic signaling induced by interferon-alpha
Author: Hjortsberg, Linn
Date: 2007-04-27
Location: Radiumhemmets föreläsningssal, Karolinska Universitetssjukhuset, Solna
Time: 10.00
Department: Institutionen för onkologi-patologi / Department of Oncology-Pathology
View/ Open:
thesis.pdf (4.707Mb)
Abstract
Interferon-alpha (IFNalpha) is a pleiotropic cytokine which has been used
as an active drug in the treatment of malignant diseases for almost five
decades. It has shown beneficial results in several hematological
malignancies, as well as solid tumors, including hairy cell leukemia,
multiple myeloma, chronic myeloid leukemia, renal carcinoma and malignant
melanoma. However, many tumors do not respond or develop resistance to
the effects of IFNalpha. Understanding of the molecular mechanisms of the
anti-tumor effects of IFNalpha is crucial for the development of
efficient treatment regimens and functional combination treatments.
In this thesis the molecular mechanism of IFNalpha stimulated apoptosis
was investigated. Upstream signals which lead to the activation of
mitochondrial events in apoptotic cell death were studied in detail to
delineate the requirement of classical JAK/STAT signaling as well as
neoclassical stress induced signaling.
By using chemical inhibitors and/or over-expression of dominant negative
mutant proteins, we showed that PI3K/mTOR is required for the
pro-apoptotic action of IFNalpha. We identified a small set of five
genes, which require both STAT- and P13K signaling to be up-regulated by
IFNalpha. Therefore we suggest that the products of these genes may play
a role in the apoptotic response to IFNalpha.
Furthermore, we established that PKCdelta, ERK and JNK are sequentially
activated by IFN, downstream of PI3K/mTOR. Inhibition of these kinases
reduced the signs of apoptosis, as measured by phosphatidyl serine
exposure, loss of deltapsimit, release of cytochrome c and caspase
activation. Despite efficient inhibition of cell death, no alterations
could be observed in STAT phosphorylation, translocation or overall
transactivation. By studying enucleated cells (cytoplast) we found that
IFNalpha induced cell death can occur also in the absence of IFNalpha
induced gene activation.
In conclusion, we have shown that the pro-apoptotic mechanisms of
IFNalpha depend mainly on direct activation of latent cytoplasmic
signaling molecules, independent of de novo transcription of IFN
regulated genes. We also suggest that STAT proteins are required for the
onset of IFNalpha stimulated apoptosis, and that nuclear events may
potentiate the response.
List of papers:
I. Thyrell L, Hjortsberg L, Arulampalam V, Panaretakis T, Uhles S, Dagnell M, Zhivotovsky B, Leibiger I, Grander D, Pokrovskaja K (2004). "Interferon alpha-induced apoptosis in tumor cells is mediated through the phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway." J Biol Chem 279(23): 24152-62. Epub 2004 Mar 31
Pubmed
II. Hjortsberg L, Lindvall C, Corcoran M, Arulampalam V, Chan D, Thyrell L, Nordenskjold M, Grander D, Pokrovskaja K (2007). "Phosphoinositide 3-kinase regulates a subset of interferon-alpha-stimulated genes." Exp Cell Res 313(2): 404-14. Epub 2006 Oct 27
Pubmed
III. Panaretakis T, Hjortsberg L, Pokrovskaja K, Bjorklund A, Joseph B, Grander D (2007). "Interferon-alpha induces nucleus-independent apoptosis by activating ERK1/2 and JNK downstream of PI3K and TOR." (Submitted)
IV. Hjortsberg L, Pokrovskaja K, Bjorklund A, Yang Z, Arulampalam V, Grander D (2007). "Importance of STAT-signaling in interferon-alpha induced apoptosis." (Manuscript)
I. Thyrell L, Hjortsberg L, Arulampalam V, Panaretakis T, Uhles S, Dagnell M, Zhivotovsky B, Leibiger I, Grander D, Pokrovskaja K (2004). "Interferon alpha-induced apoptosis in tumor cells is mediated through the phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway." J Biol Chem 279(23): 24152-62. Epub 2004 Mar 31
Pubmed
II. Hjortsberg L, Lindvall C, Corcoran M, Arulampalam V, Chan D, Thyrell L, Nordenskjold M, Grander D, Pokrovskaja K (2007). "Phosphoinositide 3-kinase regulates a subset of interferon-alpha-stimulated genes." Exp Cell Res 313(2): 404-14. Epub 2006 Oct 27
Pubmed
III. Panaretakis T, Hjortsberg L, Pokrovskaja K, Bjorklund A, Joseph B, Grander D (2007). "Interferon-alpha induces nucleus-independent apoptosis by activating ERK1/2 and JNK downstream of PI3K and TOR." (Submitted)
IV. Hjortsberg L, Pokrovskaja K, Bjorklund A, Yang Z, Arulampalam V, Grander D (2007). "Importance of STAT-signaling in interferon-alpha induced apoptosis." (Manuscript)
Issue date: 2007-04-06
Rights:
Publication year: 2007
ISBN: 978-91-7357-186-9
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