Abstract 1130: Targeting the tumor-associated autoantigen alpha-enolase in prostate cancer

Abstract

Abstract Prostate cancer (PCa) is the most commonly diagnosed cancer and second leading cause of cancer-related deaths in American men. African American (AA) men are more likely to be diagnosed with aggressive PCa at a younger age and twice as likely to die from the disease as European American (EA) men. In order to reduce PCa mortality and its associated racial disparities, there is a critical need to identify and target pathways responsible for PCa aggressiveness. An unexplored target is the plasminogen system, which is key to cancer cell migration and tissue invasion during metastasis. During inflammation, activation of the plasminogen pathway degrades extracellular fibrin networks; however, in the context of cancer, this activation promotes cancer tissue invasion and metastasis. Mounting evidence shows that the glycolytic enzyme alpha-enolase (ENO1) plays a vital role in both increased energy metabolism and plasminogen activation during cancer progression and metastasis. Using immunoseroproteomic profiling of anti-tumor autoantibody responses in AA and EA men with PCa, we identified several tumor-associated autoantigens with functions in glycolysis and plasminogen signaling, including ENO1, annexin A2, fructose bisphosphate aldolase, glucose-regulated protein 78, glyceraldehyde-3-phosphate dehydrogenase and phosphoglycerate kinase. In a cohort of PCa (N=157) and non-PCa sera (N=183), we found a significantly higher frequency of autoantibodies to ENO1 in patients with PCa (p<0.05). Surprisingly, when we probed a panel of non-PCa and PCa cell lines with anti-ENO1 positive sera from AA and EA patients with PCa, we observed that AA patients showed increased immunoreactivity to this protein in metastatic PCa cells, with decreased reactivity in docetaxel-resistant cell lines. By contrast, the anti-ENO1 EA-PCa sera and a monoclonal mouse anti-ENO1 showed relatively uniform immunoreactivity across the same panel cell lines. This suggested that the AA-PCa patients are producing antibodies to a different ENO1 variant than EA-PCa patients. Proteomic analysis of post-translational modifications (PTM) in ENO1 showed differences in ENO1 PTM profiles between the parental PC3 bone metastatic cell line and the PC3 docetaxel-resistant cell line, which could explain the differential autoantibody reactivity observed in AA men. Given that ENO1 is up-regulated in PCa tissue, plays a role in glucose metabolism and plasminogen activation during cancer progression, and that the immune system of a cohort of AA-PCa patients recognizes an alternately modified variant of ENO1 that is upregulated in metastatic PCa, we elected to target this protein in metastatic PCa cell lines. ENO1 depletion via siRNA knockdown in PC3 cells led to increased cell death, with concomitant decrease in PCa proliferation. Taken together, these results highlighted the value of immunoproteomics as a tool to identify novel therapeutic targets, with ENO1 as a promising target in metastatic PCa. Citation Format: Tino Wilson Sanchez, Guangyu Zhang, Jitian Li, Liping Dai, Saied Mirshahidi, Nathan R. Wall, Clayton Yates, Colwick Wilson, Susanne Montgomery, Jian-Ying Zhang, Carlos A. Casiano. Targeting the tumor-associated autoantigen alpha-enolase in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1130. doi:10.1158/1538-7445.AM2017-1130