This proposal focuses on elucidating the function of Raf Kinase Inhibitor Protein, RKIP, a novel kinase inhibitor that was identified as a potent tumor metastasis suppressor in vitro, and whose transcription regulation - by Snail and/or EZH2 (Enhancer of Zeste Homolog 2) - we hypothesize is key to understanding signaling pathways involved in prostate cancer progression and metastasis. Mechanistically, this protein functions as a negative regulator of both the Raf and NF-_B signaling pathways. Consistent with its inhibitory effects on these two pathways, a significant inverse correlation was observed between the expression of RKIP and the stage of cancer development in prostate tumors. Particularly, high levels of RKIP were noted in healthy prostate tissue, whereas these levels progressively decreased to almost undetectable levels in prostate tissues of increasing aggressiveness and metastatic capability. Importantly, restoration of RKIP expression in highly metastatic prostate cancer cell lines sensitized them to apoptosis and inhibited metastasis in a xenograft mouse model, suggesting this protein as a promising candidate for cancer therapy. In order to utilize this potential, the present application proposes to define the transcription factors that regulate RKIP expression (Specific Aim #1) and establish its physiological relevance in vivo (Specific Aim #2). Particularly, Specific Aim #1 will examine the possible roles of the transcription factors Snail and EZH2 in regulating RKIP expression in prostate cancer. This will be done by both loss-of-function and gain-of-function approaches, as well as through a combination of genetic and biochemical methods.
Specific Aim #2 will study a possible in vivo role of Snail and EZH2 as regulators of RKIP expression in prostate cancer, using DNA and tissue microarray (TMA) studies to correlate between the expression of RKIP and the two abovementioned transcription factors in samples from prostate cancer patients. Carcinoma of the prostate is the most common malignancy among males in the US. This proposal should provide a new handle for understanding its etiology in molecular detail and initiate studies aimed at dissecting the complex regulatory transcriptional network that is responsible for downregulation of RKIP. The information gained from this research offers a promising potential for both prostate cancer therapy, as well as other cancers.

Public Health Relevance

Prostate cancer, although curable in early stages, is often not diagnosed until the cancer has spread and become refractory to chemotherapy. Our proposed study of the tumor metastasis suppressor protein RKIP will potentially lead to a better understanding of the molecular mechanism of metastasis and chemoresistance in advanced prostate cancer and possibly pave the way for a new therapeutic approach.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Sathyamoorthy, Neeraja
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Toledo
Schools of Medicine
United States
Zip Code
Cho, Anne Arah; Bonavida, Benjamin (2017) Targeting the Overexpressed YY1 in Cancer Inhibits EMT and Metastasis. Crit Rev Oncog 22:49-61
Wottrich, Stephanie; Kaufhold, Samantha; Chrysos, Emmanuel et al. (2017) Inverse correlation between the metastasis suppressor RKIP and the metastasis inducer YY1: Contrasting roles in the regulation of chemo/immuno-resistance in cancer. Drug Resist Updat 30:28-38
Bonavida, B; Chouaib, S (2017) Resistance to anticancer immunity in cancer patients: potential strategies to reverse resistance. Ann Oncol 28:457-467
Kaufhold, Samantha; Garbán, Hermes; Bonavida, Benjamin (2016) Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication. J Exp Clin Cancer Res 35:84
Bonavida, Benjamin; Kaufhold, Samantha (2015) Prognostic significance of YY1 protein expression and mRNA levels by bioinformatics analysis in human cancers: a therapeutic target. Pharmacol Ther 150:149-68
Datar, Ila; Feng, Jingwei; Qiu, Xiaoliang et al. (2015) RKIP Inhibits Local Breast Cancer Invasion by Antagonizing the Transcriptional Activation of MMP13. PLoS One 10:e0134494
Bonavida, Benjamin (2014) RKIP-mediated chemo-immunosensitization of resistant cancer cells via disruption of the NF-?B/Snail/YY1/RKIP resistance-driver loop. Crit Rev Oncog 19:431-45
Datar, Ila; Tegegne, Hanna; Qin, Kevin et al. (2014) Genetic and epigenetic control of RKIP transcription. Crit Rev Oncog 19:417-30
Ren, Gang; Baritaki, Stavroula; Marathe, Himangi et al. (2012) Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer. Cancer Res 72:3091-104
Kou, Geng; Shi, Jingping; Chen, Lin et al. (2010) A bispecific antibody effectively inhibits tumor growth and metastasis by simultaneous blocking vascular endothelial growth factor A and osteopontin. Cancer Lett 299:130-6

Showing the most recent 10 out of 12 publications