Trevor M. Penning, Ph.D.
University of Pennsylvania Perelman School of Medicine
1315 BRB II/III
421 Curie Blvd
Philadelphia, PA 19104-6160
Fax: (215) 573-0200
Lab: (215) 898-1144
B.Sc. (Physiology and Biochemistry)
(First Class Honors) Southampton University, UK, 1972.
Southampton University, UK, 1976.
Description of Research ExpertiseResearch Summary
Steroid Hormone Transforming Aldo-Keto Reductases.
The aldo-keto reductase (AKR) superfamily contains mammalian hydroxysteroid dehydrogenases (HSDs). For each sex steroid there are a pair of HSDs, which by acting as reductases or oxidases can convert potent steroid hormones into their cognate inactive metabolites or vice versa. When found in steroid target tissues they can regulate the occupancy and trans-activation of steroid hormone receptors, providing a pre-receptor regulation of steroid hormone action. Many HSDs are considered therapeutic targets. For example, aldo-keto reductase AKR1C3 (type 5 17beta-hydroxysteroid dehydrogenase) catalyses the formation of the potent androgens, testosterone and 5alpha-dihydrotestosterone, in castrate resistant prostate cancer (CRPC). CRPC is dependent upon intratumoral androgen biosynthesis that reactivate the androgen receptor and is uniformly fatal. Structure-based inhibitor design is being used to develop selective AKR1C3 inhibitors for the treatment of CRPC. In another area structure-function studies on steroid 5beta-reductase (AKR1D1)are being pursued. This enzyme catalyzes a pivotal step in bile-acid biosynthesis and natural mutations are causal in bile-acid deficiency syndromes which are often neonatal fatal. In both areas we use the following techniques: site-directed mutagenesis, x-ray crystallography, transient and steady state kinetics, and transfection studies in prostate cancer cell lines.
Dihydrodiol Dehydrogenases and Polycyclic Aromatic Hydrocarbon (PAH) Activation
Dihydrodiol dehydrogenases are members of the AKR superfamily. They convert PAH-trans-dihydrodiols (proximate carcinogens) to reactive and redox active o-quinones. By entering into futile redox-cycles the o-quinones can amplify the production of reactive oxygen species (e.g., superoxide anion, hydrogen peroxide and hydroxyl radical). The pro-oxidant state may provide a mechanism by which PAH can act as complete carcinogens. Similar metabolic activation has been observed for the structurally related catechol estrogens and diethylstilbestrol. The cytotoxicity and genotoxicity of PAH o-quinones are being studied in human lung cells as it pertains to causality in human lung cancer. Methods include cell culture, high-resolution NMR, EPR, mass-spectrometry, PAH-DNA adduct chemistry, and mutagenesis paradigms.
Ms. Ling Duan, MS Laboratory Manager
Dr. Tianzhu (Indy) Zang
Dr. Juliette Aka
Ms. Jessica Murray
Ms. Isabelle Lee
Also, visit www.med.upenn.edu/akr
Selected PublicationsChen M, Wangtrakuldee P, Zang T, Duan L, Gathercole LL, Tomlinson JW, Penning TM.: Human and murine steroid 5β-reductases (AKR1D1 and AKR1D4): insights into the role of the catalytic glutamic acid. Chem. Biol. Interact. 305: 163-170, May 2019.
Verma K, Zang T, Penning TM, Trippier PC.: Potent and Highly Selective Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors Act as Chemotherapeutic Potentiators in Acute Myeloid Leukemia and T-Cell Acute Lymphoblastic Leukemia. J. Med. Chem. 62(7): 3590-3916, April 2019.
Mostaghel EA, Zhang A, Hernandez S, Marck BT, Zhang X, Tamae D, Biehl HE, Tretiakova M, Bartlett J, Burns J, Dumpit R, Ang L, Matsumoto AM, Penning TM, Balk SP, Morrissey C, Corey E, True LD, Nelson PS.: Contribution of Adrenal Glands to Intratumor Androgens and Growth of Castration-Resistant Prostate Cancer. Clin.Cancer Res. 25(1): 426-439, Jan 2019.
Wangtrakuldee P, Adeniji AO, Zang T, Duan L, Khatri B, Twenter BM, Estrada MA, Higgins TF, Winkler JD, Penning TM.: A 3-(4-nitronaphthen-1-yl) amino-benzoate analog as a bifunctional AKR1C3 inhibitor and AR antagonist: Head to head comparison with other advanced AKR1C3 targeted therapeutics. J. Steroid Biochem. Mol. Biol. Epub ahead of Print: doi: 10.1016/j.jsbmb.2019.01.001, Jan 2019.
Murray JR, Mesaros CA, Arlt VM, Seidel A, Blair IA, Penning TM.: Role of Human Aldo-Keto Reductases in the Metabolic Activation of the Carcinogenic Air Pollutant 3-Nitrobenzanthrone. Chem. Res. Toxicol. 11 : 1277-1288, Nov 2018.
Sullivan J, Croisant S, Howarth M, Rowe GT, Fernando H, Phillips-Savoy A, Jackson D, Prochaska J, Ansari GAS, Penning TM, Elferink C; Community Partner Authors: Louisiana Environmental Action Network, United Houma Nation, Bayou Interfaith Shared Community Organizing, Dustin Nguyen-Vietnamese Community Partner, Center for Environmental & Economic Justice, and Alabama Fisheries Cooperative Project Community Scientist Author: Wilma Subra.: Building and Maintaining a Citizen Science Network With Fishermen and Fishing Communities Post Deepwater Horizon Oil Disaster Using a CBPR Approach. New Solutions 28(3): 416-447, Nov 2018.
Verma K, Gupta N, Zang T, Wangtrakluldee P, Srivastava SK, Penning TM, Trippier PC.: AKR1C3 Inhibitor KV-37 Exhibits Antineoplastic Effects and Potentiates Enzalutamide in Combination Therapy in Prostate Adenocarcinoma Cells. Mol Cancer Ther. 17(9): 1833-1845, Epub 2018 Jun 11 2018.
Huang J, Liu Y, Vitale S, Penning TM, Whitehead AS, Blair IA, Vachani A, Clapper ML, Muscat JE, Lazarus P, Scheet P, Moore JH, Chen Y.: On meta- and mega-analyses for gene-environment interactions. Genet Epidemiol. 41: 876-886, 2017.
Zang, T., Taplin, M.E., Tamae, D., Xie, W., Mesaros, C., Zhang, Z., Bubley, G., Montgomery, B., Balk, S.P., Mostaghel, E.A., Blair, I.A. and Penning, T.M. : Testicular versus Adrenal Sources of Hydroxyandrogens in Prostate Cancer. Endocr Relat Cancer. 24: 393-404, 2017.
Huang M, Mesaros C, Hackfeld LC, Hodge RP, Zang T, Blair IA, Penning TM. : Potential Metabolic Activation of a Representative C4-Alkylated Polycyclic Aromatic Hydrocarbon Retene (1-Methyl-7-isopropyl-phenanthrene) Associated with the Deepwater Horizon Oil Spill in Human Hepatoma (HepG2) Cells. Chem. Res. Toxicol. 30: 1093-1101, 2017.