Background: Prostate cancer is the most common non-cutaneous malignancy for men in the U.S. Patients with advanced and/or metastatic prostate cancer are commonly treated with androgen deprivation therapy. Unfortunately, incurable castration resistant prostate cancer commonly develops 2-3 years after initial treatment.
Methods: To identify candidate cancer genes involved in the development of castration resistance, the Sleeping Beauty (SB) transposon system and androgen-sensitive LNCaP cell line were used in a forward mutagenesis screen designed to model the transition from androgen sensitive to androgen insensitive prostate cancer. MAGI-2 was identified in the screen as a common insertion site gene, potentially involved in the transition to androgen independence. Clinical significance of MAGI-2 in prostate cancer was further supported by human TCGA data. Functional assays were used to confirm the involvement of MAGI-2 in prostate cancer progression.
Results: MAGI-2 expression was prognostic for patient survival outcome. Ectopic expression of MAGI-2 in 22Rv1 cells resulted in a decrease in cell proliferation and colony formation in in vitro studies. At the molecular level, overexpression of MAGI2 induced a suppression of known androgen responsive genes. MAGI-2 overexpression also limited the growth of grafts compared to empty vector grafts in in vivo xenograft models.
Conclusion: MAGI-2 was identified in a forward mutagenesis screen modeling the development of castration resistant prostate cancer. Human protein expression data from patient tissues supported a possible role for MAGI-2 in prostate cancer. Functional studies confirmed the potential involvement of MAGI-2 in prostate cancer progression. Future studies are seeking to elucidate the functional role and mechanism-of-action for MAGI-2 in prostate cancer. Ultimately, this may identify MAGI-2-regulated signaling pathways as therapeutic targets for prostate cancer.
Citation Format: Bao Le, Kimberly Hammer, Katya Frantskevich, Irene Ong, Wei Huang, Paul Marker. Role of membrane-associated guanylate kinase inverted 2 in advanced and castration-resistant prostate cancers [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 3401. doi:10.1158/1538-7445.AM2017-3401