This application is built upon extensive progress made during the past five years in understanding the role of IKK? and various inflammatory and immune mechanisms in the control of metastatic progression in prostate cancer (PCa) and the development of castration-resistant tumors after androgen ablation. We found that accumulation of activated IKK? in nuclei of PCa cells is required both for metastatic dissemination and development of castration resistance. IKK? exerts its nuclear effects, in part, through transcriptional activation of the Bmi1 gene, which encodes a component of Polycomb repressive complex 1 (PRC1), as well as through repression of the metastasis inhibitor maspin. Nuclear accumulation of activated IKK? was also observed in human PCa and Bmi-1 is a key regulator of PCa stem cell renewal in both humans and mice. Therefore, we will use mouse models and human clinical specimens to investigate the mechanisms through which activated IKK? accumulates in nuclei of PCa cells and how it stimulates Bmi1 transcription. Interference with these mechanisms will offer new approaches to PCa therapy, that are supported by our preliminary results, which demonstrate inhibition of prostate stem cell activation upon loss of IKK? kinase activity and that the combination of IKK? inhibition and androgen receptor blockade completely prevents castration resistance. In PCa cells, IKK? is activated by inflammatory cytokines that are produced by immune cells which are recruited into the tumors during normal progression and after androgen ablation. We found that activated myofibroblasts are the critical source of the chemokines that recruit cytokine-producing immune cells into prostate tumors under both conditions. We will therefore study the mechanisms responsible for myofibroblast activation, both in response to androgen ablation and during normal tumor progression. We will also investigate the role of myofibroblasts in metastatic progression. Correspondingly, five specific aims will be pursued: 1) Define the mechanisms through which IKK? stimulates Bmi1 transcription in collaboration with E2F transcription factors;2) Determine whether IKK? represses the SPB5 (Maspin) gene through its effect on Bmi-1 expression;3) Investigate the mechanisms responsible for the nuclear accumulation of activated IKK? in PCa cells and find ways to inhibit IKK? nuclear accumulation;4) Determine the role of myofibroblasts and their origin during metastatic progression of PCa;5) Define mechanisms that are responsible for myofibroblast activation and appearance during development of castration-resistant cancer and metastatic progression. In addition to explaining basic mechanisms that account for PCa metastasis and emergence of castration resistance, the proposed research will lead to development of new therapeutic strategies for interference with these major causes of PCa-associated morbidity and mortality.

Public Health Relevance

Metastatic spread, especially to bone, and castration resistant disease are the two major causes of mortality associated with prostate cancer. This project will examine basic mechanisms that control prostate cancer metastasis and castration resistance by focusing on regulatory processes that take place within prostate cancer cells in response to signals that emanate from their microenvironment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Medicine
La Jolla
United States
Zip Code
Febbraio, Mark A; Reibe, Saskia; Shalapour, Shabnam et al. (2018) Preclinical Models for Studying NASH-Driven HCC: How Useful Are They? Cell Metab :
Shalapour, Shabnam; Lin, Xue-Jia; Bastian, Ingmar N et al. (2017) Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 551:340-345
Shalapour, Shabnam; Font-Burgada, Joan; Di Caro, Giuseppe et al. (2015) Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 521:94-8
Shalapour, Shabnam; Karin, Michael (2015) Immunity, inflammation, and cancer: an eternal fight between good and evil. J Clin Invest 125:3347-55
Ammirante, Massimo; Shalapour, Shabnam; Kang, Youngjin et al. (2014) Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts. Proc Natl Acad Sci U S A 111:14776-81
Ammirante, Massimo; Kuraishy, Ali I; Shalapour, Shabnam et al. (2013) An IKK?-E2F1-BMI1 cascade activated by infiltrating B cells controls prostate regeneration and tumor recurrence. Genes Dev 27:1435-40
Zhang, Weizhou; Tan, Wei; Wu, Xuefeng et al. (2013) A NIK-IKK? module expands ErbB2-induced tumor-initiating cells by stimulating nuclear export of p27/Kip1. Cancer Cell 23:647-59
Li, Ning; Grivennikov, Sergei I; Karin, Michael (2011) The unholy trinity: inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell 19:429-31
Kuraishy, Ali; Karin, Michael; Grivennikov, Sergei I (2011) Tumor promotion via injury- and death-induced inflammation. Immunity 35:467-77
Tan, Wei; Zhang, Weizhou; Strasner, Amy et al. (2011) Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470:548-53

Showing the most recent 10 out of 12 publications