Abstract
We have previously demonstrated that extracellular adenosine 5'-triphosphate (ATP) promotes breast cancer cell chemoresistance. However, the underlying mechanism remains unclear. Using a cDNA microarray, we demonstrated that extracellular ATP can stimulate hypoxia-inducible factor (HIF) signaling. In this study, we report that hypoxia-inducible factor 1α (HIF-1α) was upregulated after ATP treatment and mediated the ATP-driven chemoresistance process. We aimed to investigate the mechanisms and identify potential clinically relevant targets that are involved. Using mass spectrometry, we found that aldolase A (ALDOA) interacts with HIF-1α and increases HIF-1α expression. We then demonstrated that STAT3-ALDOA mediates ATP-HIF-1α signaling and upregulates the HIF-1 target genes adrenomedullin (ADM) and phosphoinositide-dependent kinase-1 (PDK1). Moreover, we show that PI3K/AKT acts upstream of HIF-1α in ATP signaling and contributes to chemoresistance in breast cancer cells. In addition, HIF-1α-knockdown or treatment with direct HIF inhibitors combined with the ATP hydrolase apyrase in MDA-MB-231 cells induced enhanced drug sensitivity in nude BALB/c mice. We then used in vitro spheroid formation assays to demonstrate the significance of ATP-HIF-1α in mediating chemoresistance. Furthermore, considering that indirect HIF inhibitors are effective in clinical cancer therapy, we treated tumor-bearing BALB/c mice with STAT3 and PI3K/AKT inhibitors and found that the dual-targeting strategy sensitized breast cancer to cisplatin. Finally, using breast cancer tissue microarrays, we found that ATP-HIF-1α signaling is associated with cancer progression, poor prognosis, and resistance to chemotherapy. Taken together, we suggest that HIF-1α signaling is vital in ATP-driven chemoresistance and may serve as a potential target for breast cancer therapies.
Highlights
Extracellular adenosine 5'-triphosphate (ATP) is considered to be an important messenger in mediating cell survival, proliferation, and migration, and it can act as a chemotactic molecule for the recruitment of immune phagocytes [1]
hypoxia-inducible factor (HIF)-1α mediates ATP-driven chemoresistance in vitro We have demonstrated that extracellular ATP can regulate HIF signaling by elevating HIF-1/2α expression in a time- and dosedependent manner [13]
Evidence suggests that ATP [14] and hypoxia-inducible factor 1α (HIF-1α) are closely associated with breast cancer chemoresistance [23] as well as drug resistance in multiple other carcinomas [24, 25]
Summary
Extracellular adenosine 5'-triphosphate (ATP) is considered to be an important messenger in mediating cell survival, proliferation, and migration, and it can act as a chemotactic molecule for the recruitment of immune phagocytes [1]. A large increase in the concentration of extracellular ATP in the tumor microenvironment (TME) has been identified as a malignant tumor phenotype [2]. Evidence suggests that extracellular ATP can regulate tumor growth and shape the TME directly by acting through receptors, mainly through P2 purinergic receptors on both tumor and host cells [5, 6]. Over the past several decades, we demonstrated that extracellular ATP could promote cancer cell invasion via the P2Y2 and P2X7 receptors to regulate epithelial-mesenchymal transition (EMT) and invasion-associated molecules, including IL-8, E-cadherin, Snail, Claudin-1, β-catenin, S100A4, HIF-2α, and SOX9, as well as through activation of epidermal growth factor receptor (EGFR) and extracellular signalregulated kinase 1/2 (ERK1/2) signaling [7–14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
