Extracellular ATP promotes breast cancer invasion and chemoresistance via SOX9 signaling

Our previous research demonstrated that extracellular adenosine 5'-triphosphate (ATP) could promote breast cancer cell invasion. However, the impact of extracellular ATP on chemoresistance and the mechanisms behind ATP pro-invasion and pro-chemoresistance remain unclear. Here we aimed to determine the molecules or signaling pathways involved. cDNA microarray was performed to identify the differentially expressed genes before and after ATP treatment. As a result, Sex-determining region Y-box 9 (SOX9) was up-regulated after ATP treatment in breast cancer cells. In vitro invasion and migration assays demonstrated that knocking down SOX9 attenuated ATP-driven invasive capability. Mass spectrometry and co-IP revealed that SOX9 interacted with Janus kinase 1 (JAK1). Afterward, IL-6-JAK1-STAT3 signaling was demonstrated to promote SOX9 expression and invasion following ATP treatment. Notably, ATP-IL-6-SOX9 signaling was shown to stimulate chemoresistance in breast cancer cells. ChIP assays identified some potential SOX9 target genes, among which carcinoembryonic antigen-related cell adhesion molecule 5/6 (CEACAM5/6) was demonstrated to mediate ATP pro-invasive function, while ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) mediated ATP-driven chemoresistance. In addition, SOX9-knockdown and apyrase (an ATP hydrolase)-treated MDA-MB-231 cells illustrated decreased tumor growth and enhanced drug sensitivity in nude mice. In vitro spheroid formation assays also proved the significance of ATP-SOX9 in mediating chemoresistance. Moreover, molecules involved in ATP-SOX9 signaling were up-regulated in human breast carcinoma specimens and were associated with poor prognosis. Altogether, SOX9 signaling is vital in ATP-driven invasion and chemoresistance, which may serve as a potential target for breast cancer therapies.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:39

Enthalten in:

Oncogene - 39(2020), 35 vom: 28. Aug., Seite 5795-5810

Sprache:

Englisch

Beteiligte Personen:

Yang, Hui [VerfasserIn]
Geng, Yue-Hang [VerfasserIn]
Wang, Peng [VerfasserIn]
Yang, Han [VerfasserIn]
Zhou, Yan-Ting [VerfasserIn]
Zhang, Hong-Quan [VerfasserIn]
He, Hui-Ying [VerfasserIn]
Fang, Wei-Gang [VerfasserIn]
Tian, Xin-Xia [VerfasserIn]

Links:

Volltext

Themen:

8L70Q75FXE
Adenosine Triphosphate
Journal Article
Research Support, Non-U.S. Gov't
SOX9 Transcription Factor
SOX9 protein, human

Anmerkungen:

Date Completed 07.01.2021

Date Revised 09.02.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1038/s41388-020-01402-z

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM312998678