Tryptophan hydroxylase 1 and 5-HT7 receptor preferentially expressed in triple-negative breast cancer promote cancer progression through autocrine serotonin signaling

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Abstract

Background

Triple-negative breast cancer (TNBC) has a high risk of relapse and there are few chemotherapy options. Although 5-hydroxytryptamine (5-HT, serotonin) signaling pathways have been suggested as potential targets for anti-cancer drug development, the mechanism responsible for the action of 5-HT in TNBC remains unknown.

Methods

Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to measure mRNA and protein levels, respectively. Cell proliferation was measured using CellTiter 96 Aqueous One Solution. siRNA transfection was used to assess involvement of genes in cancer invasion, which were identified by Matrigel transwell invasion assay. Levels of 5-HT and vascular endothelial growth factor (VEGF) were measured using ELISA kits. Chick chorioallantoic membrane (CAM) assay and mouse tumor model were used to investigate the in vivo effects of SB269970, a 5-HT ₇ receptor antagonist, and BJ-1113, a novel synthetic compound.

Results

TNBC cell lines (MDA-MB-231, HCC-1395, and Hs578T) expressed higher levels of tryptophan hydroxylase 1 (TPH1) than hormone-responsive breast cancer cell lines (MCF-7 and T47D). In MDA-MB-231 cells, 5-HT promoted invasion and proliferation via 5-HT ₇ receptor, and interestingly, the stimulatory effect of 5-HT on MDA-MB-231 cell invasion was stronger than its effect on proliferation. Likewise, downstream signaling pathways of 5-HT ₇ differed during invasion and proliferation, that is, Gα-activated cAMP and Gβγ-activated kinase signaling during invasion, and Gβγ-activated PI3K/Akt signaling during proliferation. Also, 5-HT increased the protein expressions of TPH1 and VEGF in MDA-MB-231 cells. These results provide insight of the stimulatory effect of 5-HT on breast cancer progression; 5-HT was found to act more strongly during the first stage of metastasis (during invasion and migration) than during the later proliferative phase after local invasion. Interestingly, these actions of 5-HT were inhibited by BJ-1113, a 6-amino-2,4,5-trimethylpyridin-3-ol analog. BJ-1113 blocked intracellular signaling pathways initiated by 5-HT ₇ receptor activation, and exhibited anti-proliferative and anti-invasive activities against MDA-MB-231 cells. Furthermore, the inhibitory effect of BJ-1113 against MDA-MB-231 tumor growth was greater than that of SB269970, a 5-HT ₇ receptor antagonist.

Conclusions

5-HT ₇ receptor which mediates 5-HT-induced cancer progression is a potential therapeutic target in TNBC, and BJ-1113 offers a novel scaffold for the development of anti-cancer agents against TNBC.

Related collections

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Author and article information

Contributors

Jaya Gautam: jayagautam@ynu.ac.kr

Suhrid Banskota: suhrid@ynu.ac.kr

Sushil Chandra Regmi: sushilregmi@ynu.ac.kr

Subi Ahn: tnql2541@naver.com

Yong Hyun Jeon: jeon9014@empal.com

Hyunyoung Jeong: yjeong@uic.edu

Seung Joo Kim: sjkim0605@hanmail.net

Tae-gyu Nam: tnam@hanyang.ac.kr

Byeong-Seon Jeong: +82-53-810-2814 , jeongb@ynu.ac.kr

Jung-Ae Kim: +82-53-810-2816 , jakim@yu.ac.kr

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 21 November 2016

Publication date PMC-release: 21 November 2016

Publication date Collection: 2016

Volume: 15

Electronic Location Identifier: 75

Affiliations

[1 ]College of Pharmacy, Yeungnam University, 280 Daehak-Ro, Gyeongsan, 38541 Republic of Korea

[2 ]Department of Nuclear Medicine, Kyungpook National University, Daegu, 41944 Republic of Korea

[3 ]Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612 USA

[4 ]Department of Pharmacy, Hanyang University, Ansan, 15588 Republic of Korea

Article

Publisher ID: 559

DOI: 10.1186/s12943-016-0559-6

PMC ID: 5117586

PubMed ID: 27871326

SO-VID: 3903db62-c6ed-4887-9b38-4ccdd94ff760

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 23 June 2016

Date accepted : 14 November 2016

Funding

Funded by: National Research Foundation of Korea (NRF)

Award ID: NRF-2014R1A2A2A01006833

Award Recipient : Jung-Ae Kim

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: triple negative breast cancer,autocrine 5-ht action,tryptophan hydroxylase 1,5-ht7 receptor,6-amino-2,4,5-trimethylpyridin-3-ol

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: triple negative breast cancer, autocrine 5-ht action, tryptophan hydroxylase 1, 5-ht7 receptor, 6-amino-2,4,5-trimethylpyridin-3-ol