Enzymes and Coenzymes Commons^™

Human Kallikrein 2: A Novel Lineage-Specific Surface Target In Prostate Cancer, Fei Shen, Ryan Smith, Theresa Mcdevitt, Krista Menard, Shaozhou Tian, Gerald Chu, Ruchi Chaudhary, Jennifer Mccann, Halley Oyer, Sherry C. Wang, Steven Max, Peter Francis, William K. Kelly, Charles G. Drake

Kimmel Cancer Center Faculty Papers

PURPOSE: Targeted therapies for metastatic prostate cancer are limited, highlighting the need for novel drug targets and mechanisms of action (MoA). Human kallikrein 2 (KLK2) is a prostate-specific antigen expressed across the prostate cancer disease continuum. However, it was not recognized as a therapeutic target for prostate cancer in the past due to limited evidence of its cell surface expression. In this study, we systematically characterized KLK2 expression in prostate cancer, confirmed its cell surface expression, and demonstrated the preclinical efficacy of three KLK2-targeting therapeutics with distinct MoA.

EXPERIMENTAL DESIGN: The KLK2 expression profile in different stages of prostate cancer …

Gatad2b O-Glcnacylation Regulates Breast Cancer Stem-Like Potential And Drug Resistance, Giang Le Minh, Jessica Merzy, Emily Esquea, Nusaiba Ahmed, Riley Young, Ryan Sharp, Tejsi Dhameliya, Bernice Agana, Mi-Hye Lee, Jennifer Bethard, Susana Comte-Walters, Lauren Ball, Mauricio Reginato

Kimmel Cancer Center Faculty Papers

The growth of breast tumors is driven and controlled by a subpopulation of cancer cells resembling adult stem cells, which are called cancer stem-like cells (CSCs). In breast cancer, the function and maintenance of CSCs are influenced by protein O-GlcNAcylation and the enzyme responsible for this post-translational modification, O-GlcNAc transferase (OGT). However, the mechanism of CSCs regulation by OGT and O-GlcNAc cycling in breast cancer is still unclear. Analysis of the proteome and O-GlcNAcome, revealed GATAD2B, a component of the Nucleosome Remodeling and Deacetylase (NuRD) complex, as a substrate regulated by OGT. Reducing GATAD2B genetically impairs mammosphere formation, decreases expression …

Nrf2/Cyclooxygenase 2 Signaling In Cr(Vi)-Induced Carcinogenesis, Lei Zhao, Yi-Fang Wang, Andrea Adamcakova-Dodd, Peter Thorne, Ranakul Islam, Ke Jian Liu, Fei Chen, Jia Luo, Ling-Zhi Liu

Kimmel Cancer Center Faculty Papers

Long-term exposure to hexavalent chromium [Cr(VI)] has been linked to lung cancer, and cyclooxygenase-2 (COX-2) is a well-known inflammatory factor. However, the role and mechanism of COX-2 in Cr(VI)-induced carcinogenesis are not clear yet. To address this question, we employed a mouse model exposed to Cr(VI) through intranasal instillation of particulate zinc chromate (ZnCrO4) for 12 weeks. Metabolomics and RNA-seq assays revealed enhanced activity of the arachidonic acid (AA)/eicosanoid metabolism pathway in lung tissues from mice exposed to Cr(VI). COX-2, the key enzyme of the AA/eicosanoid pathway, was significantly upre- gulated in Cr(VI)-exposed lung tissues, as well as in the …

Selective And Brain-Penetrant Acss2 Inhibitors Target Breast Cancer Brain Metastatic Cells, Emily Esquea, Lorela Ciraku, Riley Young, Jessica Merzy, Alexandra Talarico, Nusaiba Ahmed, Mangalam Karuppiah, Anna Ramesh, Adam Chatoff, Claudia Crispim, Adel Rashad, Simon Cocklin, Nathaniel Snyder, Joris Beld, Nicole Simone, Mauricio Reginato, Alexej Dick

Kimmel Cancer Center Faculty Papers

Breast cancer brain metastasis (BCBM) typically results in an end-stage diagnosis and is hindered by a lack of brain-penetrant drugs. Tumors in the brain rely on the conversion of acetate to acetyl-CoA by the enzyme acetyl-CoA synthetase 2 (ACSS2), a key regulator of fatty acid synthesis and protein acetylation. Here, we used a computational pipeline to identify novel brain-penetrant ACSS2 inhibitors combining pharmacophore-based shape screen methodology with absorption, distribution, metabolism, and excretion (ADME) property predictions. We identified compounds AD-5584 and AD-8007 that were validated for specific binding affinity to ACSS2. Treatment of BCBM cells with AD-5584 and AD-8007 leads to …