Faculty Profile: Wayne Bowen, Ph.D., Cornell University, 1981

Wayne Bowen
Wayne Bowen, Ph.D., Cornell University, 1981
Dept. Chair, Professor of Biology, Upjohn Professor of Pharmacology
Molecular Pharmacology, Physiology & Biotechnology
Work: +1 401-863-3253
We study sigma receptors, proteins found throughout the body. They bind several classes of psychoactive drugs. Activation of sigma-2 receptors causes programmed cell death (apoptosis). We are trying to understand the underlying mechanisms for this. Because they are highly expressed in cancer cells, we are targeting sigma-2 receptors for development of new antineoplastic agents. Also, antipsychotic drugs such as haloperidol damage neurons via sigma-2 receptors. Blocking sigma-2 receptors might prevent the irreversible motor side effects caused by typical neuroleptic agents.

Biography

Dr. Wayne Bowen earned his B.S. in chemistry from Morgan State College in 1974, and completed his Ph.D. in biochemistry and neurobiology at Cornell University in 1981. After postdoctoral studies at the National Institute of Mental Health (NIMH), he initially came to Brown University in 1983, as Assistant Professor of Biology in the Section of Biochemistry where he taught endocrinology, introductory biology, and biochemistry and did research on opioid and sigma receptors in the brain. Shortly after promotion to Associate Professor, he moved back to the NIH in 1991 to establish the Unit on Receptor Biochemistry and Pharmacology within the Laboratory of Medicinal Chemistry of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). He returned to Brown University in 2004 to take his current position as Professor of Biology in the Department of Molecular Pharmacology, Physiology & Biotechnology in the Division of Biology and Medicine. In 2007, he assumed the position as department chair and was named Upjohn Professor of Pharmacology in 2008.

Dr. Bowen is a nationally recognized leader in research on sigma receptors—membrane proteins found in tissues throughout the body and that are highly upregulated in cancer cells. He has shown that activation of sigma-2 receptors induces apoptotic cell death, and therefore they may serve as regulators of cell proliferation and survival. He is interested in signal transduction, particularly those pathways that lead to receptor-mediated cell death. Trained initially as a chemist, he maintains a strong interest and involvement in medicinal chemistry and drug design, particularly in relation to development of selective sigma receptor agonists and antagonists. He is exploring these compounds as potential anti-neoplastic, tumor diagnostic, and neuroprotective agents.

Dr. Bowen currently co-directs the medical school's pharmacology course, teaches in endocrinology and neuroscience courses for undergraduates, and co-directs the core pharmacology course for the Molecular Pharmacology and Physiology Graduate Program. Dr. Bowen is a member of the Society for Neuroscience, the International Brain Research Organization/World Federation of Neuroscientists, and the American Association for Cancer Research. He is the recipient of numerous awards and honors, and has performed service on NIMH and NIDA Study Sections. He served as president of the NIH Black Scientists Association in 2001. Dr. Bowen's research has been funded by NIDA, NINDS, NIDDK, the Rhode Island Science and Technology Advisory Council, and a Salomon Award from Brown University.

Institutions

Brown Medical School

Research Description

Pharmacology and medicinal chemistry of sigma receptors and opioid receptors

Sigma receptors as therapeutic and diagnostic targets.

Sigma receptors and drug-induced apoptosis.

Signal transduction mechanisms in receptor-mediated apoptosis and regulation of cell proliferation.

Small molecule drug design.


My general interests have centered on biochemical mechanisms involved in the action of opiate drugs, opioid peptides, and related compounds. Current research in this laboratory is directed at elucidation of the structure and function of sigma receptors. Sigma receptors (formerly classified as opioid receptors) are membrane-bound proteins that recognize several important classes of psychotropic drugs, including antipsychotic agents such as haloperidol, the psychotomimetic agent phencyclidine (PCP), some synthetic opiates such as pentazocine, and some psychostimulants like cocaine. Sigma-1 and sigma-2 receptor subtypes are currently known, and likely comprise a novel receptor family distinct from any known neurotransmitter or hormone receptor system. Both subtypes are present in the CNS as well as in peripheral tissues, and are expressed in high density in a number of neuronal and non-neuronal tumor cell lines. No endogenous ligands for these receptors have yet been clearly identified, although there is existing evidence for such substances and progesterone and other neurosteroids have been shown to interact with sigma-1 receptors.

Most work in our laboratory currently focuses on the possible role of sigma-2 receptors in regulation of cell proliferation and survival. We have found that chronic activation of sigma-2 receptors induces apoptosis in a wide variety of cell types. We are investigating the signaling mechanisms leading to the induction of cell death, and have found that these mechanisms are cell type-specific. For example, in breast tumor cells, apoptosis occurs via a novel mechanism that is both caspase- and p53-independent, whereas in a neuroblastoma line, cell death is dependent on caspase 8/10 activation. Signaling involves both transient and sustained changes in cytosolic calcium levels. We are interested in determining the mechanisms of calcium flux and the downstream effects of these calcium signals. Signaling also involves changes in cellular sphingolipids (ceramides and lysosphingolipids). Sphingolipids are involved in myriad cellular processes including cell survival, regulation of ion channels, and cell-cell recognition. Lysosphingolipids act via specific G-protein coupled receptors on the cell surface, as well as through certain intracellular targets, and ceramides are known to modulate the activity of various protein kinases and phosphatases involved in cell growth. We are investigating the role of sphingolipid signaling in neuronal and non-neuronal cells and how this system interfaces with sigma-2 receptors. Also under investigation are effects of sigma-2 receptor activation on mitochondria. Apoptosis in both neuronal and non-neuronal cell types appears to be dependent on loss of mitochondrial membrane potential and release of mitochondrial apoptogenic factors. The roles of mitochondrial pro- and anti-apoptotic Bcl-2 family proteins are under study. Finally, the sigma-2 receptor, a 21.5 kDa lipid raft protein, has not yet been cloned. We have projects underway aimed at purifying sigma-2 receptor proteins, obtaining protein sequence information, and using this information to clone the sigma-2 receptor gene.

The sigma-1 receptor has been cloned and is a 25 kDa polypeptide with two putative transmembrane domains. In contrast to sigma-2 receptors, activation of sigma-1 receptors appears to exert protective and perhaps trophic effects on neurons and other cell types. Others have shown that activation of sigma-1 receptors potentiates neurite outgrowth in culture, whereas we have shown that activation of sigma-2 receptors causes neurite retraction. Blockade of sigma-1 receptors by selective antagonists or antisense deoxyoligonucleotides has been shown to block the toxic effects of cocaine, a psychotropic agent that binds to sigma-1 receptors. Furthermore, sigma-1 receptor activation in the hippocampus has a cognitive enhancing effect. We have initiated structure-function studies of the sigma-1 receptor and its role in tumor cell proliferation and survival. Sigma-1 receptors regulate calcium signaling by amplifying release of calcium from the endoplasmic reticulum in response to the rise in IP3 via GPCR activation. The sigma-1 receptor appears to signal solely by protein-protein interactions. The liganded receptor binds to ankyrin in the ER membrane and relieves a tonic inhibition of the IP3 receptor that is imparted by its interaction with ankyrin. We have shown that stable overexpression of sigma-1 receptors induces a constitutive activation of the IP3 receptor in human MCF-7 breast tumor cells, which are normally devoid of sigma-1 receptors. Furthermore, studies using various receptor constructs showed that only the C-terminal segment of the receptor is required for this effect. We are further delineating the functional domains of the receptor. Furthermore, cells overexpressing active sigma-1 constructs proliferate more rapidly than untransfected cells and have a survival advantage. We are investigating the signaling mechanisms that are involved in inducing what appears to be a more highly aggressive phenotype. The studies suggest that the sigma-1 receptor could be a biomarker for assessing proliferative status of tumor cells.

We are involved in the design and synthesis of novel small molecule ligands for sigma-1 and sigma-2 receptors. Since the natural ligand(s) is unknown and many existing sigma ligands interact with other receptors, selective synthetic probes for sigma receptors are necessary. Through close collaboration with medicinal chemists, we have developed and are continuing to develop highly selective receptor agonists and antagonists for use as tools to study receptor function. We are interested in elucidating the structural features of ligands that determine binding affinity, impart subtype selectivity, and that specify agonist/antagonist properties. Some of these compounds may have clinical potential as therapeutic agents.

Studies of sigma receptors will shed light on novel modes for regulation of cell proliferation and survival. It may be possible to target sigma-2 receptors with agonists or sigma-1 receptors with antagonists to induce apoptosis in tumors rendered drug-resistant due to acquisition of mutations in key components of the classical apoptotic pathway, such as p53 and caspases. Sigma receptors in the CNS could conceivably play a role in neurodegenerative disorders. Furthermore, since typical neuroleptics such as haloperidol activate sigma-2 receptors, these studies may have important implications for treatment of psychiatric disorders with respect to the debilitating motor side effects induced by these agents.

Grants and Awards

  • Dean's List Morgan State College (1970-1974)

  • Promethean Kappa Tau Freshman Honor Society (1971)

  • Most Outstanding Sophomore Chemistry Major Award (1972)

  • Analytical Chemistry Award (1973)

  • Beta Kappa Chi National Scientific Honor Society (1973)

  • Alpha Kappa Mu National Honor Society (1973)

  • Graduated Morgan State College Summa Cum Laude (1974)

  • Outstanding Young Men of America (1986)

  • Men of Achievement (1989)

  • Delivered Biology Concentration Commencement Address, Brown University (1990)

  • Ad Eundem Honorary Degree, Brown University (1990)

  • Recognition Award, Daniel Hale Williams Medical Society and Office of Minority Medical Affairs, Brown University Division of Biology and Medicine (May 1991)

  • Sterling's Who's Who (1996)

  • Award of Appreciation, Keynote Address, Science-Mathematics-Engineering Fair, Morgan State University (March 23, 1996)

  • Certificate of Appreciation, Student and Teacher Internship Program, Howard Hughes Medical Institute, Montgomery County Public Schools, and National Institutes of Health (1996-1997)

  • Certificate of Recognition, NIH Speakers Bureau, National Institutes of Health (June 12, 2000)

  • Special Recognition Award, Discussion with a Scientist Series, Undergraduate Scholarship Program, National Institutes of Health (2000)

  • Award of Recognition for Research in Receptor Biochemistry and Pharmacology, Keynote Address, Undergraduate and Graduate Science Research Symposium, Morgan State University (April 18, 2002)

  • President, NIH Black Scientists Association (2001)

  • Nominated for 2006 AACR-Minorities in Cancer Research—Jane C. Wright Lectureship Award (American Association for Cancer Research)

  • Jack and Linda Gill Lecturer - Indiana University, 2007

  • ISI Highly Cited Researcher

Affiliations

Society for Neuroscience
International Brain Research Organization/World Federation of Neuroscientists
American Association for Cancer Research

Funded Research

I. PAST SUPPORT

a. Completed Intramural Research Support

NIH/NIDDK Intramural Research Program 09/1991 – 08/2004
PI: W.D. Bowen
Structure and Function of Sigma Receptors

b. NIH Grants (while at Brown before move to NIH intramural program in 1991)

National Institute on Drug Abuse
"Identification and Analysis of Opiate Receptor Proteins"
R01 DA03776
Principal Investigator: Wayne D. Bowen (33.3% effort)
6/1/85 - 3/31/92
To purify and structurally analyze kappa opiate receptors.

Division of Research Resources
BRS Shared Instrumentation Grant
S10 RR03381-01
"Peptide Synthesizer and Peptide Sequencer"
Principal Investigator: Wayne D. Bowen
4/1/87 - 3/31/88: $101,000
Used to establish a macromolecular biochemistry core facility at Brown University.

National Institute of Neurological Disorders and Stroke
"Role of Sigma Receptors in Movement Disorders"
R01 NS26746
Principal Investigator: Wayne D. Bowen (33.3% effort)
12/1/88 - 11/30/91
To study biochemical systems modulated by sigma receptors in vitro and physiological systems modulated by these receptors in vivo, with particular emphasis on the role of sigma receptors in dystonia

National Institute on Drug Abuse
"Sigma Opiate Receptor Pharmacology"
R01 DA04988
Principal Investigator: J. Michael Walker
Co-Principal Investigator: Wayne D. Bowen (10% effort)
10/1/88 - 8/31/91
Studies of the basic pharmacology of the sigma receptor, including studies of its regulation by chronic neuroleptic treatment and verification of in vitro and in vivo models of sigma activity.

National Institute on Drug Abuse
"Development of Selective Sigma Receptor Ligands"
R01 DA05721
Principal Investigator: Frank I. Carroll, Research Triangle Institute
Co-Principal Investigator: Wayne D. Bowen (5% effort with Brown University Subcontract)
9/1/89 - 8/31/92
To conduct computer modelling studies for prediction of structural requirements for drugs specific to the sigma receptor.

Division of Research Resources
BRS Shared Instrumentation Grant
"Molecular Graphics Workstation"
Principal Investigator: J.W. Suggs, Department of Chemistry, Brown University
7/89 - 6/90
$83,000 (no salary, no supplies)
To establish workstations for molecular modelling studies.


II. COLLABORATIONS ON NIH GRANTS (named as "Collaborator" under personnel after move to NIH intramural program in 1991):

National Institute on Drug Abuse
"Development of Selective Sigma Receptor Ligands"
R01 DA05721
Principal Investigator: Frank I. Carroll, Research Triangle Institute,
Department of Chemistry and Life Sciences
Collaborator: Wayne D. Bowen
9/1/92 - 3/31/99
Design of potent and selective sigma ligands based on the benzomorphan structure, with particular emphasis on design of sigma-2-selective compounds.

National Institute of Mental Health
"Sigma Receptor Subtypes and Motor Side Effects"
R29 FIRST Award, MH50564
Principal Investigator: Rae Matsumoto, University of Oklahoma Health Sciences Center,
Department of Pharmacology and Toxicology, College of Pharmacy
Collaborators: Wayne D. Bowen and Brian R. de Costa
To study the role of sigma receptor subtypes in the cerebellorubro-spinal motor system and to characterize the action of putative sigma agonists and antagonists in this system.

National Cancer Institute
"Novel Diagnostic Agents for Imaging Malignant Melanoma"
R29 FIRST Award (R29 CA58496)
Principal Investigator: Christy John, George Washington University Medical Center,
Division of Nuclear Medicine
Collaborator: Wayne D. Bowen
5/94 - 4/99
To develop new radiodiagnostic agents for imaging human malignant melanoma micro-metastasis using SPECT and PET. To investigate the utility of sigma receptors as tumor markers for radioimaging.

National Cancer Institute
"Sigma Receptor-Specific Radiopharmaceuticals for Imaging Human Tumors"
R01 CA70784
Principal Investigator: Christy John, George Washington University Medical Center,
Division of Nuclear Medicine
Collaborator: Wayne D. Bowen
7/1/97 - 6/30/00
To develop non-invasive SPECT imaging agents for human breast cancer.

National Institute on Drug Abuse
"Sigma Ligands for the Treatment of Cocaine Overdose"
Principal Investigator: Rae Matsumoto, University of Oklahoma Health Sciences Center,
Department of Pharmacology and Toxicology, College of Pharmacy
Collaborator: Wayne D. Bowen
To investigate the ability of sigma antagonists to attenuate the toxic effects of cocaine and to develop potential compounds for treatment.


III. PAST SUPPORT: Brown University, Private Foundations, Industry

Biomedical Research Support Grant (Brown University)
"The Opiate Receptor: Identification and Purification of Ligand Binding Subunits"
Principal Investigator: Wayne D. Bowen
7/1/83 - 3/31/84 $2,000

Rhode Island Foundation
"Multiple Opiate Receptor Types: Purification of Ligand Binding Sites and Analysis of Subunit Structure"
Principal Investigator: Wayne D. Bowen
7/10/84 - 7/10-85 $3,180

Rhode Island Foundation
"Multiple Opiate Receptor Types: Purification of Ligand Binding Sites and Analysis of Subunit Structure"
Principal Investigator: Wayne D. Bowen
7/10/85 - 7/10-86 $3,500

Biomedical Research Support Grant (Brown University)
"The Biochemical Role of Opiates and Opioid Peptides in the Central Nervous System"
Principal Investigator: Wayne D. Bowen
4/1/85 - 3/31/86 $5,500

Biomedical Research Support Grant (Brown University)
"Effect of Opiates on Phosphoinositide Metabolism and Protein Kinase C Activity in Rat Brain"
Principal Investigator: Wayne D. Bowen
4/1/86 - 3/31/87 $3,500

Dystonia Medical Research Foundation
"Sigma Receptors and Dystonia"
Principal Investigators: Wayne D. Bowen and J.M. Walker (J.M.W.; Department of Psychology, Brown University)
3/1/87 - 2/28/89: $26,617 first year, $27,109 second year, direct costs only; no salary.
To study sigma ligand-induced alterations in motor function and alterations in binding properties of sigma receptors in mutant dystonic rats.

Biomedical Research Support Grant (Brown University)
"Modulation of Agonist-Stimulated Phosphoinositide Turnover by Sigma Receptors in Brain and PC12 Cells"
Principal Investigator: Wayne D. Bowen
6/1/88 - 8/31/88 $6,837
To investigate the possibility of functional sigma receptor heterogeneity by comparison of phophoinositide modulation in brain and PC12 cells.

Monsanto-Searle Pharmaceuticals
Joint Research Collaborative Agreement Between Brown, NIH, and Monsanto-Searle
$5,000
To characterize novel ligands for sigma and PCP receptors in biochemical assay systems.

2007 Salomon Award, Office of Vice President for Research, Brown University 2007 - 2008
PI: W.D. Bowen
"Correlation of Sigma-1 Receptor Expression and Function with Indicators of Tumor Aggressiveness and Metastatic Potential" - $15,000


IV. CURRENT AND PENDING SUPPORT:

National Institute on Drug Abuse
R21DA022326-01A2 04/01/08 - 03/31/10
PI: W. Peti; Co-PI: W.D. Bowen
"Structure of the Sigma-1 Receptor"
The major goals of this project are to determine the solution structure of the sigma-1 receptor using NMR spectroscopy and to delineate the functional domains.

Brown University Division of Biology and Medicine
Start-up funds – 9/1/04 – present

Teaching Experience

Wayne Bowen has been teaching since 1983. He began with teaching introductory biology and endocrinology at Brown University. He later provided neuroscience lectures to undergraduate students, which he is still doing today. He has also taught biochemistry seminar courses to graduate students. While at NIH, he chaired the Department of Pharmacology and Toxicology of the NIH-Foundation for Advanced Education in the Sciences (FAES) Graduate School (1999 - 2004). He is currently co-directing the pharmacology component of the Integrated Pathophysiology/Pharmacology course in the Brown University Medical School. Over the course of his career, he has advised over 40 undergraduates in research projects in his laboratory. He has served as a Human Biology concentration advisor in the Health and Disease and Brain and Behavior tracks. He has directed the research of 4 graduate students and 11 postdoctoral fellows.

Courses Taught

  • Directed Research/Independent Studies (BIOL 1950)
  • Directed Research/Independent Studies (BIOL 1960)
  • Endocrinology (BIOL 0030)
  • Graduate Independent Study (BIOL 2980)
  • Independent Study (NEUR 1970)
  • Integrated Medical Sciences III – System-Based Pharmacology; course Co-Director (BIOL 3667)
  • Integrated Medical Sciences IV – System-Based Pharmacology; course Co-Director (BIOL 3676)
  • Receptor, Channels and Signaling (BIOL 2170)
  • The Brain: An Introduction to Neuroscience (NEUR 0010)

Selected Publications

  • Wei, Z., Qi, J., Dai, Y., Bowen, W.D., and Mousseau, D.D. (2009) Haloperidol disrupts Akt signalling to reveal a phosphorylation-dependent regulation of pro-apoptotic Bcl-XS function. Cellular Signalling 21: 161-168. (2009)
  • Liu, Q., Bhat, M., Bowen, W.D., Cheng, J. Signaling pathways from activation of CB1 receptor to inhibition of NMDA-mediated calcium influx and neurotoxicity in dorsal root ganglion neurons. J. Pharmacol. Exp. Ther. 331: 1062-1070, 2009. (2009)
  • Wu, Z. and Bowen, W.D. (2008) Role of sigma-1 receptor C-terminal segment in inositol 1,4,5-trisphosphate receptor activation: Constitutive enhancement of calcium signaling in MCF-7 tumor cells. J. Biol. Chem. 283: 28198-28215. (2008)
  • Martin-Fardon, R., Maurice, T., Aujla, H., Bowen, W.D., and Weiss, F. (2007) Diffferential effects of sigma-1 receptor blockade on self-administration and conditioned reinstatement motivated by cocaine vs. natural reward. Neuropsychopharmacol. 32: 1967-1973. (2007)
  • Gebreselassie, D. and Bowen, W.D. (2004) Sigma-2 receptors are specifically localized to lipid rafts of rat liver membranes. Eur. J. Pharmacol. 493: 19-28. (2004)
  • Matsumoto, R.R., Potelleret, F.H., Mack, A., Pouw, B., Zhang, Y., and Bowen, W.D. (2004) Structure-activity comparison of YZ-069, a novel sigma ligand, and four analogs in receptor binding and behavioral studies. Pharmacol. Biochem. Behav. 77: 775-781. (2004)
  • Romieu, P., Martin-Fardon, R., Bowen, W.D., and Maurice, T. (2003) Sigma1 receptor-related neuroactive steroids modulate cocaine-induced reward. J. Neurosci. 23: 3572-3576. (2003)
  • Cao, J.J., Kulkarni, S.S., Husbands, S.M., Bowen, W.D., Williams, W., Kopajtic, T., Katz, J.L., George, C., and Newman, A.H. (2003) Dual probes for the dopamine transporter and the sigma-1 receptors: Novel piperazinyl alkyl-bis-(4'-fluorophenyl)amine analogs as potential cocaine-abuse therapeutics. J. Med. Chem. 46: 2589-2598. (2003)
  • Crawford, K.W., Bittman, R., Chun, J., Byun, H.S., and Bowen, W.D. (2003) Novel ceramide analogs display selective cytotoxicity in drug-resistant breast tumor cell lines compared to normal breast epithelial cells. Cell. Mol. Biol. 49: 1017-1023. (2003)
  • Crawford, K.W. and Bowen, W.D. (2002) Sigma-2 receptor agonists activate a novel apoptotic pathway and potentiate antineoplastic drugs in breast tumor cell lines. Cancer Res. 62: 313-322. (2002)
  • Crawford, K.W., Coop, A., and Bowen, W.D. (2002) Sigma-2 receptors regulate changes in sphingolipid levels in breast tumor cells. Eur. J. Pharmacol. 443: 207-209. (2002)
  • Matsumoto, R.R., McCracken, K.A., Pouw, B., Zhang, Y., and Bowen, W.D. (2002) Involvement of sigma receptors in the behavioral effects of cocaine: evidence from novel ligands and antisense oligodeoxynucleotides. Neuropharmacol. 42: 1043-1055. (2002)
  • Vilner, B.J. and Bowen, W.D. (2000) Modulation of cellular calcium by sigma-2 receptors: Release from intracellular stores in human SK-N-SH neuroblastoma cells. J. Pharmacol. Exp. Ther. 292: 900-911. (2000)
  • John, C.S., Vilner, B.J., Geyer, B.C., Moody, T., and Bowen, W.D. (1999) Targeting sigma receptor-binding benzamides as in vivo diagnostic and therapeutic agents for human prostate tumors. Cancer Res. 59: 4578-4583. (1999)