Our long-term goal is to understand the transcriptional mechanisms that regulate the expression of NF?B- dependent chemokines as they relate to cancer development and progression. Interleukin-8 (IL-8, CXCL8) is a pro-inflammatory and pro-angiogenic chemokine that contributes to cancer progression through its induction of tumor cell survival, angiogenesis, and metastasis. IL-8 expression is increased in many types of advanced cancers, including ovarian (OC) and prostate (PC) cancer, and correlates with poor prognosis. There are no effective treatments for the advanced stages of ovarian and prostate cancer; thus, novel therapeutic strategies are urgently needed. Even though histone deacetylase (HDAC) inhibition by HDAC inhibitors (HDIs) and proteasome inhibition by bortezomib (BZ) have been highly effective in the treatment of cutaneous T cell lymphoma (CTCL) and other hematological cancers, they have been less effective in solid tumors, including ovarian and prostate cancer; the responsible mechanisms are not fully understood. Our preliminary studies show that while HDIs suppress the IL-8 expression in CTCL cells, they induce the IL-8 expression in solid tumors and monocytic cells. Furthermore, our results indicate that the HDI-induced IL-8 expression is partly mediated by I?B kinase (IKK), and that suppression of the HDI-induced IL-8 expression decreases survival of cancer cells. In addition, we have shown that while proteasome inhibition suppresses expression of most of the NF?B-dependent genes, it paradoxically increases the expression of IL-8 in cancer cells. Importantly, our recent in vivo data have demonstrated that combining BZ with anti- inflammatory IKK inhibitor significantly reduces ovarian tumor growth in mice when compared to either drug alone, indicating that using anti-inflammatory IKK inhibitors may increase BZ effectiveness in solid tumors. The central hypothesis, based on our preliminary data, is that anti-inflammatory therapy targeting the HDI- and BZ-induced IL-8 expression will increase HDI and BZ effectiveness in ovarian and prostate cancer. This hypothesis will be tested in two specific aims.
In Aim 1, we will determine the in vitro mechanisms by which HDAC inhibition increases the IL-8 expression in ovarian and prostate cancer cells, and in monocytic cells.
In Aim 2, we will test the hypothesis that anti-inflammatory therapy increases HDI and BZ effectiveness in reducing ovarian and prostate cancer growth in nude mice, and we will investigate the responsible in vivo mechanisms. Understanding the mechanisms by which HDAC and proteasome inhibition induces IL-8 expression will lead to the development of novel combination strategies for the treatment of ovarian and prostate cancer, and other drug resistant solid tumors characterized by excessive IL-8 release. In addition, this project will enhance the research environment at St. John's University by providing undergraduate and graduate students with numerous opportunities to learn the fundamentals of biomedical research.

Public Health Relevance

This proposal focuses on the mechanisms by which histone deacetylase (HDAC) and proteasome inhibition induces expression of the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8) in ovarian and prostate cancer. Since IL-8 promotes tumor progression and metastases, and since HDAC and proteasome inhibitors have been tested in clinical studies for the treatment of advanced stages of solid tumors including ovarian and prostate cancer, understanding the mechanisms of how HDAC and proteasome inhibitors induce the IL-8 expression will lead to the development of more effective combination anti-cancer strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15CA202775-01A1
Application #
9169773
Study Section
Special Emphasis Panel (ZRG1-IMM-T (81))
Program Officer
Yovandich, Jason L
Project Start
2016-08-15
Project End
2019-08-14
Budget Start
2016-08-15
Budget End
2019-08-14
Support Year
1
Fiscal Year
2016
Total Cost
$495,000
Indirect Cost
$195,000
Name
St. John's University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
073134744
City
Queens
State
NY
Country
United States
Zip Code
11439
Zou, Yue; Uddin, Mohammad M; Padmanabhan, Sveta et al. (2018) The proto-oncogene Bcl3 induces immune checkpoint PD-L1 expression, mediating proliferation of ovarian cancer cells. J Biol Chem 293:15483-15496
Vancurova, Ivana; Uddin, Mohammad M; Zou, Yue et al. (2018) Combination Therapies Targeting HDAC and IKK in Solid Tumors. Trends Pharmacol Sci 39:295-306
Gatla, Himavanth R; Zou, Yue; Uddin, Mohammad M et al. (2017) Epigenetic regulation of interleukin-8 expression by class I HDAC and CBP in ovarian cancer cells. Oncotarget 8:70798-70810
Vancurova, Ivana; Gatla, Himavanth R; Vancura, Ales (2017) HDAC/IKK inhibition therapies in solid tumors. Oncotarget 8:34030-34031
Gatla, Himavanth R; Zou, Yue; Uddin, Mohammad M et al. (2017) Histone Deacetylase (HDAC) Inhibition Induces I?B Kinase (IKK)-dependent Interleukin-8/CXCL8 Expression in Ovarian Cancer Cells. J Biol Chem 292:5043-5054