Glioblastoma Multiforme (GBM) is a highly invasive and malignant primary brain. Despite aggressive treatment that currently includes surgical resection followed by radiation and chemotherapy, the recurrence of GBM is high with only 3-5% patients surviving longer than 3 years. GBM is refractory to treatment because it rapidly disseminates throughout the brain, develops a tumor microenvironment with GBM-initiated proinflammatory state characterized by the presence of cytokines, such as IL-1, which are secreted by both GBM cells and GBM-activated astrocytes. Our preliminary data show that IL-1 induces expression of transcription factor interferon regulatory factor 1 (IRF-1) in astrocytes. Newly synthesized IRF-1 is subsequently activated and induces the expression of potent chemokines CCL5 and CXCL10. The mechanism of IRF-1 activation remains elusive;however, other IRFs are activated by their K63-linked polyubiquitination and phosphorylation. Our preliminary data demonstrate that IL-1 induces K63-linked polyubiquitination of IRF-1 that is needed for its activation. Although, phosphorylation of IRF-1 has been reported, it is not clear whether it is also required for IRF-1 activation. IRF-1-dependent expression of CCL5 and CXCL10 in astrocytes likely affects GBM progression. Although both of these chemokines are commonly associated with monocyte and T lymphocyte chemotaxis, they both can increase GBM proliferation. Thus, our central hypothesis is that in response to IL-1, astrocytes upregulate expression of IRF-1-dependent chemokines CXCL10 and CCL5, which promote the proliferation, migration, and invasion of GBM cells in vivo. We propose the following aims to test this hypothesis:
Aim 1 : Determine whether phosphorylation of IRF-1 is a critical step in the activation of IRF-1 by IL-1.
Aim 2 : Evaluate the effect of astrocyte-derived CCL5 and CXCL10 on GBM proliferation, migration, and invasion in vitro.
Aim 3 : Determine the role of IRF-1 in both GBM development and progression in vivo. Completion of these aims will establish whether activation of IRF-1, CXCL10, and CCL5 contributes to GBM development and progression. It may also lead to new targets for the development of therapies in the future.

Public Health Relevance

Glioblastoma Multiforme (GBM) is a highly invasive and malignant primary brain tumor that evades current aggressive treatments and initiates proinflammatory state in the brain characterized by the presence of cytokines, including IL-1. We found that IL-1 regulates expression of CCL5 and CXCL10 chemokines in astrocytes via the activation of interferon regulatory factor 1 (IRF-1) that includes its K63-linked polyubiquitinatio. Astrocyte-derived CCL5 and CXCL10 can promote the proliferation, migration, and invasion of GBM cells in vivo. Thus, understanding whether activation of IRF-1, CXCL10, and CCL5 in astrocytes contributes to GBM development and progression is critical, and may also lead to development of therapies in the future.

Agency
National Institute of Health (NIH)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30CA174231-02
Application #
8753068
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Damico, Mark W
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298