# The plasma membrane monoamine transporter (PMAT): expression and role in mIBG disposition in neuroblastoma

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $367,715

## Abstract

PROJECT SUMMARY
The long term goal of this project is to understand the physiological function of plasma membrane monoamine
transporter (PMAT) and its role in the disposition and action of xenobiotics. Previous work established PMAT
as a monoamine and organic cation transporter expressed on cell plasma membranes of normal tissues.
While the physiological function of PMAT and its role in organic cation disposition have been characterized,
little is known regarding its expression and function in diseased tissues. Recently, we and others found that
PMAT is highly expressed in human neuroblastoma (NB) tissues and cell lines. Our preliminary data suggest
that in contrast to its normal cell surface expression, PMAT is aberrantly localized in intracellular organelles in
human NB cells. The aberrant intracellular localization of PMAT in NB cells is associated with the presence
and increased expression of an alternatively spliced variant. Furthermore, we found that meta-
iodobenzylguanidine (mIBG), a radiopharmaceutical used in both diagnosis and treatment of NB, is avidly
transported by PMAT. In particular, 131I-mIBG therapy is currently under intense clinical investigation as a
frontline treatment for patients with high risk NB. Cellular uptake and retention of 131I-mIBG in tumor cells is
crucial for its anti-tumor activity. Based on these data, we hypothesized that PMAT is a novel, previously
unrecognized transporter involved in intracellular disposition and therapeutic efficacy of 131I-mIBG in NB. This
competing renewal application focuses on understanding the expression and cellular localization of PMAT in
NB and its role in systemic disposition and tumor retention of mIBG. Three specific aims are proposed. In Aim
1, we will determine the expression and precise cellular localization of PMAT in NB tissues and cells by mRNA
analysis, protein quantification, and immuno-colocalization studies. The functional significance of PMAT in
cellular mIBG disposition will be evaluated using cultured human NB cells with stable silencing of the PMAT
gene. In Aim 2, we will determine the role of the alternatively spliced variant in regulating membrane trafficking
and intracellular retention of PMAT by co-transfection and co-immunoprecipitation studies. In Aim 3, we will
determine the in vivo significance of PMAT in mIBG systemic disposition, tumor retention and response using a
Pmat knockout model and a murine xenograft model. The proposed studies will uncover a novel molecular
mechanism underlying mIBG intracellular uptake and retention in its target cells. As 131I-mIBG therapy is
currently being investigated as a frontline treatment for NB, the proposed studies will pave the way for future
clinical evaluation of PMAT as a prognostic factor in tumor disposition and response to 131I-mIBG therapy.

## Key facts

- **NIH application ID:** 9928060
- **Project number:** 5R01GM066233-16
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Joanne Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $367,715
- **Award type:** 5
- **Project period:** 2002-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928060

## Citation

> US National Institutes of Health, RePORTER application 9928060, The plasma membrane monoamine transporter (PMAT): expression and role in mIBG disposition in neuroblastoma (5R01GM066233-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9928060. Licensed CC0.

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