Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

QAP14 suppresses breast cancer stemness and metastasis via activation of dopamine D1 receptor

A Correction to this article was published on 26 January 2022

This article has been updated

Abstract

Breast cancer is the second leading cause of cancer-related mortality in women, mainly due to metastasis, which is strongly associated with cancer stemness. Our previous studies showed that the eradication of cancer stem-like cells (CSCs) may be related to the activation of dopamine D1 receptor (D1DR). This study aimed to explicitly demonstrate the target-role of D1DR activation in antimetastatic therapy and to investigate the potential efficacy and the underlying D1DR-related mechanisms of QAP14, a new oral compound. 4T1, MDA-MB-231, and D1DR-knockout 4T1 (4T1-D1DR) cells were selected for in vitro study, while 4T1 and 4T1-D1DR cells were further used to establish a mouse allograft model for in vivo study. Our results showed that D1DR is abundantly expressed in both 4T1 and MDA-MB-231 cells and that knocking out D1DR in 4T1 cells accelerated migration and invasion in vitro as well as lung metastasis in vivo. QAP14 inhibited colony formation, cell motility, mammosphere formation and CSC frequency, induced CSC apoptosis and D1DR expression, and increased cAMP/cGMP levels. Additionally, QAP14 showed inhibitory effects on tumor growth and lung metastasis with acceptable safety in vivo. Knocking out D1DR almost completely abolished the efficacy, confirming that QAP14 exhibits its anti-CSC and antimetastatic effects through D1DR activation. The underlying mechanisms involved suppression of the nuclear factor κB (NF-κB)/protein kinase B (Akt) pathway and consequent downregulation of both epithelial-to-mesenchymal transition (EMT) process and cancer stemness. In summary, our findings suggest a potential candidate compound, QAP14, as well as a potential target, D1DR, for metastatic breast cancer therapy.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: QAP14 suppressed stemness and tumor growth of metastatic breast cancer.
Fig. 2: QAP14 inhibited the motility of metastatic breast cancer cells.
Fig. 3: The anti-metastasis effect and preliminary safety evaluation of QAP14 in 4T1 allograft model.
Fig. 4: QAP14 activated D1DR in 4T1 cells.
Fig. 5: D1DR antagonist SCH partially antagonized the regulatory effects of QAP14 on metastatic breast cancer.
Fig. 6: D1DR knockout reversed the inhibitory efficacy of QAP14 on metastatic breast cancer.
Fig. 7: QAP14 regulated NF-κB/Akt pathways and EMT process in 4T1 cells.
Fig. 8: The underlying mechanisms involved in the inhibitory effects of QAP14 via D1DR activation on breast cancer metastasis to the lung.

Change history

References

  1. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331:1559–64.

    CAS  Article  Google Scholar 

  2. Gradishar WJ, Anderson BO, Abraham J, Aft R, Agnese D, Allison KH, et al. Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18:452–78.

  3. Dittmer J. Breast cancer stem cells: features, key drivers and treatment options. Semin Cancer Biol. 2018;53:59–74.

    Article  Google Scholar 

  4. Antoszczak M. A medicinal chemistry perspective on salinomycin as a potent anticancer and anti-CSCs agent. Eur J Med Chem. 2019;164:366–77.

    CAS  Article  Google Scholar 

  5. Janzer A, German NJ, Gonzalez-Herrera KN, Asara JM, Haigis MC, Struhl K. Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. Proc Natl Acad Sci USA. 2014;111:10574–9.

    CAS  Article  Google Scholar 

  6. Shan NL, Wahler J, Lee HJ, Bak MJ, Gupta SD, Maehr H, et al. Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer. J Steroid Biochem Mol Biol. 2017;173:122–9.

    CAS  Article  Google Scholar 

  7. Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C, et al. Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat. 2010;122:777–85.

    CAS  Article  Google Scholar 

  8. Sachlos E, Risueño RM, Laronde S, Shapovalova Z, Lee JH, Russell J, et al. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell. 2012;149:1284–97.

    CAS  Article  Google Scholar 

  9. Li J, Yao QY, Xue JS, Wang LJ, Yuan Y, Tian XY, et al. Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer. Acta Pharmacol Sin. 2017;38:1282–96.

    CAS  Article  Google Scholar 

  10. Yeh CT, Wu AT, Chang PM, Chen KY, Yang CN, Yang SC, et al. Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer. Am J Respir Crit Care Med. 2012;186:1180–8.

    CAS  Article  Google Scholar 

  11. Wang S, Mou Z, Ma Y, Li J, Li J, Ji X, et al. Dopamine enhances the response of sunitinib in the treatment of drug-resistant breast cancer: Involvement of eradicating cancer stem-like cells. Biochem Pharmacol. 2015;95:98–109.

    CAS  Article  Google Scholar 

  12. Hao F, Wang S, Zhu X, Xue J, Li J, Wang L, et al. Pharmacokinetic-pharmacodynamic modeling of the anti-tumor effect of sunitinib combined with dopamine in the human non-small cell lung cancer xenograft. Pharmacol Res. 2017;34:408–18.

    CAS  Article  Google Scholar 

  13. Yang L, Yao Y, Yong L, Feng Y, Su H, Yao Q, et al. Dopamine D(1) receptor agonists inhibit lung metastasis of breast cancer reducing cancer stemness. Eur J Pharmacol. 2019;859:172499.

    CAS  Article  Google Scholar 

  14. Su H, Xue Z, Feng Y, Xie Y, Deng B, Yao Y, et al. N-arylpiperazine-containing compound (C2): An enhancer of sunitinib in the treatment of pancreatic cancer, involving D1DR activation. Toxicol Appl Pharmacol. 2019;384:114789.

    CAS  Article  Google Scholar 

  15. Feng Y, Jiao P, Yan X, Xue Z, Yao Y, Yang L, et al. Compound C17 inhibits the lung metastasis of breast cancer. J Chin Pharm Sci. 2019;28:716–27.

    Article  Google Scholar 

  16. Rajendran V, Jain MV. In vitro tumorigenic assay: colony forming assay for cancer stem cells. Methods Mol Biol. 2018;1692:89–95.

    CAS  Article  Google Scholar 

  17. Cioce M, Gherardi S, Viglietto G, Strano S, Blandino G, Muti P, et al. Mammosphere-forming cells from breast cancer cell lines as a tool for the identification of CSC-like- and early progenitor-targeting drugs. Cell Cycle. 2010;9:2878–87.

    CAS  Article  Google Scholar 

  18. Borcherding DC, Tong W, Hugo ER, Barnard DF, Fox S, LaSance K, et al. Expression and therapeutic targeting of dopamine receptor-1 (D1R) in breast cancer. Oncogene. 2016;35:3103–13.

    CAS  Article  Google Scholar 

  19. Beaulieu JM, Espinoza S, Gainetdinov RR. Dopamine receptors - IUPHAR Review 13. Br J Pharmacol. 2015;172:1–23.

    CAS  Article  Google Scholar 

  20. Cherubini E, Di Napoli A, Noto A, Osman GA, Esposito MC, Mariotta S, et al. Genetic and functional analysis of polymorphisms in the human dopamine receptor and transporter genes in small cell lung cancer. J Cell Physiol. 2016;231:345–56.

    CAS  Article  Google Scholar 

  21. Yan Y, Pan J, Chen Y, Xing W, Li Q, Wang D, et al. Increased dopamine and its receptor dopamine receptor D1 promote tumor growth in human hepatocellular carcinoma. Cancer Commun (Lond). 2020;40:694–710.

  22. Bourne JA. SCH 23390: the first selective dopamine D1-like receptor antagonist. CNS Drug Rev. 2001;7:399–414.

    CAS  Article  Google Scholar 

  23. Jandaghi P, Najafabadi HS, Bauer AS, Papadakis AI, Fassan M, Hall A, et al. Expression of DRD2 is increased in human pancreatic ductal adenocarcinoma and inhibitors slow tumor growth in mice. Gastroenterology. 2016;151:1218–31.

    CAS  Article  Google Scholar 

  24. Kline CLB, Ralff MD, Lulla AR, Wagner JM, Abbosh PH, Dicker DT, et al. Role of dopamine receptors in the anticancer activity of ONC201. Neoplasia. 2018;20:80–91.

    CAS  Article  Google Scholar 

  25. Sobczuk P, Łomiak M, Cudnoch-Jędrzejewska A. Dopamine D1 receptor in cancer. Cancers. 2020;12:3232.

  26. Jiang K, Yao G, Hu L, Yan Y, Liu J, Shi J, et al. MOB2 suppresses GBM cell migration and invasion via regulation of FAK/Akt and cAMP/PKA signaling. Cell Death Dis. 2020;11:230.

    CAS  Article  Google Scholar 

  27. Kim S, Jee K, Kim D, Koh H, Chung J. Cyclic AMP inhibits Akt activity by blocking the membrane localization of PDK1. J Biol Chem. 2001;276:12864–70.

    CAS  Article  Google Scholar 

  28. Maier HJ, Schmidt-Strassburger U, Huber MA, Wiedemann EM, Beug H, Wirth T. NF-kappaB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett. 2010;295:214–28.

    CAS  Article  Google Scholar 

  29. Liu M, Sakamaki T, Casimiro MC, Willmarth NE, Quong AA, Ju X, et al. The canonical NF-kappaB pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion. Cancer Res. 2010;70:10464–73.

    CAS  Article  Google Scholar 

  30. Huber MA, Azoitei N, Baumann B, Grünert S, Sommer A, Pehamberger H, et al. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 2004;114:569–81.

    CAS  Article  Google Scholar 

  31. Butti R, Gunasekaran VP, Kumar TVS, Banerjee P, Kundu GC. Breast cancer stem cells: Biology and therapeutic implications. Int J Biochem Cell Biol. 2019;107:38–52.

    CAS  Article  Google Scholar 

  32. Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem. 2000;275:36803–10.

    CAS  Article  Google Scholar 

  33. Babaei G, Aziz SG, Jaghi NZZ. EMT, cancer stem cells and autophagy; the three main axes of metastasis. Biomed Pharmacother. 2020;133:110909.

    Article  Google Scholar 

  34. Taurin S, Alkhalifa H. Breast cancers, mammary stem cells, and cancer stem cells, characteristics, and hypotheses. Neoplasia. 2020;22:663–78.

  35. Manuel Iglesias J, Beloqui I, Garcia-Garcia F, Leis O, Vazquez-Martin A, Eguiara A, et al. Mammosphere formation in breast carcinoma cell lines depends upon expression of E-cadherin. PLoS One. 2013;8:e77281.

    Article  Google Scholar 

  36. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555–67.

    CAS  Article  Google Scholar 

  37. Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN, et al. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci USA. 2012;109:2784–9.

    CAS  Article  Google Scholar 

  38. Guo Y, Yao Q, Kong D, Xue J, Yong L, Li J, et al. Development and validation of a highly sensitive HPLC-MS/MS method for the QAP14, a novel potential anti-cancer agent, in rat plasma and its application to a pharmacokinetic study. J Pharm Biomed Anal. 2020;189:113487.

    CAS  Article  Google Scholar 

  39. Pulaski BA, Ostrand-Rosenberg S. Mouse 4T1 breast tumor model. Curr Protoc Immunol. 2001; Chapter 20: Unit 20.2.

Download references

Acknowledgements

This project was supported by the Beijing Municipal Natural Science Foundation (Grant No. 7192100) and National Natural Science Foundation of China (Grant No. 82073919).

Author information

Authors and Affiliations

Authors

Contributions

Study conception and design: TYZ and LY; data acquisition: LY, GSC, XXY, YCG, and MYH; data analysis and interpretation: LY, YY, and JSX; manuscript drafting: LY, YY, and WZJ; critical revision: TYZ.

Corresponding author

Correspondence to Tian-yan Zhou.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yong, L., Yao, Y., Chen, Gs. et al. QAP14 suppresses breast cancer stemness and metastasis via activation of dopamine D1 receptor. Acta Pharmacol Sin 43, 1001–1012 (2022). https://doi.org/10.1038/s41401-021-00701-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41401-021-00701-9

Keywords

  • metastatic breast cancer
  • dopamine D1 receptor
  • cancer stemness
  • lung metastasis
  • cell motility
  • QAP14

Further reading

Search

Quick links