Empagliflozin mediated miR-128-3p upregulation promotes differentiation of hypoxic cancer stem-like cells in breast cancer.

Autor: Nalla LV; Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gujarat, India; Department of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram, AP, India., Khairnar A; Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gujarat, India; International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic ICRC, FNUSA Brno, Czech Republic; Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 735/5, 625 00, Brno, Czech Republic. Electronic address: amitkhairnar520@gmail.com.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2023 Mar 15; Vol. 943, pp. 175565. Date of Electronic Publication: 2023 Feb 03.
DOI: 10.1016/j.ejphar.2023.175565
Abstrakt: Aims: The hsa-miR-128-3p expression is downregulated in advanced breast cancer patients. Empagliflozin (EMPA) is an anti-diabetic drug with anticancer potential. The present study investigated the effect of EMPA on cancer cell differentiation by acting as a miR-128-3p mimicking drug in breast cancer.
Main Methods: Our results first demonstrate SP1 and PKM2 as the downstream effectors of hsa-miR-128-3p. Further, transfection with siPKM2, miR-128-3p mimics, and inhibitors was performed to assess their involvement in cancer stemness using flow cytometry. Further, EMPA as miR-128-3p mimicking drug was screened and explored on cancer cell differentiation. Then, we treated the 4T1-Red-FLuc allograft breast tumor with EMPA to assess its inhibitory potential toward tumor growth using IVIS® Spectrum. Immunohistochemistry was performed to evaluate cancer cell differentiation and cell proliferation.
Key Findings: We found that hsa-miR-128-3p is the upstream regulator of SP1 and PKM2 in hypoxic breast cancer cells. Overexpression of miR-128-3p with mimics downregulate SP1 and PKM2, whereas miR-128-3p inhibitor shows an opposite effect. The enhanced expression of miR-128-3p and PKM2 knockdown diminishes hypoxia-induced CD44 expression and enhance CD44 + /CD24 + differentiated cells. We also identified EMPA as the miR-128-3p mimicking drug that can enhance the differentiated cell population. Further, EMPA suppressed in vivo tumor growth, lung metastasis, tumor bioluminescence, and cell proliferation. Therefore, EMPA abrogates breast cancer stemness by inactivating SP1 and PKM2 via enhanced miR-128-3p expression.
Significance: EMPA could be a promising drug in combination with other chemotherapeutic drugs in advanced breast cancer.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: