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1. Hypoxia-Inducible Expression of Annexin A6 Enhances the Resistance of Triple-Negative Breast Cancer Cells to EGFR and AR Antagonists

Author

Stephen D. Williams, Tunde M. Smith, LaMonica V. Stewart, and Amos M. Sakwe

Subjects
hypoxia, annexin A6, triple-negative breast cancer, EGFR, Lapatinib, androgen receptor, Cytology, QH573-671
Abstract

Physiological changes such as hypoxia in the tumor microenvironment (TME) endow cancer cells with malignant properties, leading to tumor recurrence and rapid progression. Here, we assessed the effect of hypoxia (1% Oxygen) on the tumor suppressor Annexin A6 (AnxA6) and the response of triple-negative breast cancer (TNBC) cells to epidermal growth factor receptor (EGFR) and androgen receptor (AR) targeted therapies. We demonstrate that brief exposure of TNBC cells to hypoxia (within 24 h) is associated with down regulation of AnxA6 while > 24 h exposure cell type dependently stimulated the expression of AnxA6. Hypoxia depicted by the expression and stability of HIF-1/2α led to up regulation of the HIF target genes SLC2A1, PGK1 as well as AR and the AR target genes FABP-4 and PPAR-γ, but the cellular levels of AnxA6 protein decreased under prolonged hypoxia. Down regulation of AnxA6 in TNBC cells inhibited, while AnxA6 over expression enhanced the expression and cellular levels of HIF-1/2α, SLC2A1 and PGK1. RNAi mediated inhibition of hypoxia induced AnxA6 expression also strongly inhibited glucose uptake and ROS production in AnxA6 expressing TNBC cells. Using a luciferase reporter assay, we confirm that short-term exposure of cells to hypoxia inhibits while prolonged exposure of cells to hypoxia enhances AnxA6 promoter activity in HEK293T cells. Compared to cells cultured under normoxia, TNBC cells were more resistant to lapatinib under hypoxic conditions, and the downregulation of AnxA6 sensitized the cells to EGFR as well as AR antagonists. These data suggest that AnxA6 is a hypoxia inducible gene and that targeting AnxA6 upregulation may be beneficial in overcoming TNBC resistance to EGFR and/or AR targeted therapies.

Published
2022
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2. Abstract 3266: The KDM5 inhibitor PBIT reduces proliferation of castration-resistant prostate cancers via the induction of senescence

Author

Tunde M. Smith, Zhenbang Chen, and LaMonica V. Stewart

Subjects
Cancer Research, Oncology
Abstract

The members of the KDM5 family of lysine demethylases are best known for their ability to demethylate di- and trimethylated histone H3 at lysine 4 (H3K4me3). However, recent studies suggest at least three family members (KDM5A, KDM5B and KDM5C) promote prostate cancer growth and progression and may serve as effective therapeutic targets for this disease. Previous work from our laboratory has shown that 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT), a compound that inhibits the enzymatic activity of multiple KDM5 isoforms, reduces the viability of castration-resistant prostate cancer cells. The goal of this study was to further characterize the anti-tumor effects of PBIT within human prostate cancers. Two models of human castration-resistant prostate cancer were used to define the effects of PBIT: the androgen receptor (AR) positive C4-2B cells and the PC3 cells, which express little to no AR. Our group initially demonstrated via quantitative RT-PCR analysis that PC3 and C4-2B cells express varying amounts of KDM5A, KDM5B, and KDM5C, the therapeutic targets of PBIT. Presto Blue assays were next performed to determine the extent to which PBIT alters cell proliferation. Micromolar concentrations of PBIT significantly reduced prostate cancer cell proliferation in a time- and concentration-dependent manner. Data from Cell Death ELISAs suggest that PBIT at a concentration of 10 μM did not significantly induce apoptosis within C4-2B or PC3 cells. However, PBIT does appear to induce cellular senescence within the PC3 cell line. The level of senescence associated beta-galactosidase staining was increased in PC3 cells following treatment with 10 μM PBIT. Furthermore, PBIT increased protein levels of a second senescence marker, lamin B1. Together, these data suggest that the induction of senescence contributes to the anti-proliferative effect of PBIT. Citation Format: Tunde M. Smith, Zhenbang Chen, LaMonica V. Stewart. The KDM5 inhibitor PBIT reduces proliferation of castration-resistant prostate cancers via the induction of senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3266.

Published
2022
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