J 2023

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

NALLA, Lakshmi Vineela and Amit Suresh KHAIRNAR

Basic information

Original name

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

Authors

NALLA, Lakshmi Vineela and Amit Suresh KHAIRNAR (356 India, guarantor, belonging to the institution)

Edition

European Journal of Pharmacology, AMSTERDAM, Elsevier, 2023, 0014-2999

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30104 Pharmacology and pharmacy

Country of publisher

Netherlands

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

Impact factor

Impact factor: 5.000 in 2022

RIV identification code

RIV/00216224:14110/23:00131027

Organization unit

Faculty of Medicine

DOI

UT WoS

000944731500001

Keywords in English

Stemness; Breast cancer; Empagliflozin; miR-128-3p; PKM2; CD44; CD24

Tags

Tags

International impact, Reviewed
Změněno: 21/6/2023 10:47, Mgr. Tereza Miškechová

Abstract

V originále

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 involve-ment 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 (R) Spectrum. Immunohistochemistry was per-formed 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.