Oncotarget

Research Papers:

Oncogenic effects of urotensin-II in cells lacking tuberous sclerosis complex-2

Alexander A. Goldberg, Kwang-Bo Joung, Asma Mansuri, Yujin Kang, Raquel Echavarria, Ljiljana Nikolajev, Yang Sun, Jane J. Yu, Stephane A. Laporte, Adel Schwertani and Arnold S. Kristof _

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Oncotarget. 2016; 7:61152-61165. https://doi.org/10.18632/oncotarget.10748

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Abstract

Alexander A. Goldberg1,2, Kwang-Bo Joung1,2, Asma Mansuri1,2, Yujin Kang1,2, Raquel Echavarria1,2, Ljiljana Nikolajev3,4, Yang Sun5, Jane J. Yu5, Stephane A. Laporte3,4, Adel Schwertani6, Arnold S. Kristof1,2

1Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Montreal, Quebec, Canada

2Department of Critical Care Medicine, McGill University Health Centre Research Institute, Montreal, Quebec, Canada

3Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada

4Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada

5College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA

6Division of Cardiology, Montreal General Hospital, Montreal, Quebec, Canada

Correspondence to:

Arnold S. Kristof, email: [email protected]

Keywords: TSC2, mTOR, urotensin, lymphangioleiomyomatosis, angiomyolipoma

Received: May 20, 2016     Accepted: July 01, 2016     Published: July 21, 2016

ABSTRACT

Lymphangioleiomyomatosis (LAM) is a destructive lung disease that can arise sporadically or in adults suffering from the tumor syndrome tuberous sclerosis complex (TSC). Microscopic tumors (‘LAM nodules’) in the lung interstitium arise from lymphatic invasion and metastasis. These consist of smooth muscle-like cells (LAM cells) that exhibit markers of neural crest differentiation and loss of the tumor suppressor protein ‘tuberous sclerosis complex-2’ (TSC2). Consistent with a neural phenotype, expression of the neuropeptide urotensin-II and its receptor was detected in LAM nodules. We hypothesized that loss of TSC2 sensitizes cells to the oncogenic effects of urotensin-II. TSC2-deficient Eker rat uterine leiomyoma ELT3 cells were stably transfected with empty vector or plasmid for the expression of TSC2. Urotensin-II increased cell viability and proliferation in TSC2-deficient cells, but not in TSC2-reconstituted cells. When exposed to urotensin-II, TSC2-deficient cells exhibited greater migration, anchorage-independent cell growth, and matrix invasion. The effects of urotensin-II on TSC2-deficient cells were blocked by the urotensin receptor antagonist SB657510, and accompanied by activation of Erk mitogen-activated protein kinase and focal adhesion kinase. Urotensin-II-induced proliferation and migration were reproduced in TSC2-deficient human angiomyolipoma cells, but not in those stably expressing TSC2. In a mouse xenograft model, SB657510 blocked the growth of established ELT3 tumors, reduced the number of circulating tumor cells, and attenuated the production of VEGF-D, a clinical biomarker of LAM. Urotensin receptor antagonists may be selective therapeutic agents for the treatment of LAM or other neural crest-derived neoplasms featuring loss of TSC2 or increased expression of the urotensin receptor.


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