Salinomycin Promotes Anoikis and Decreases the CD44+/CD24- Stem-Like Population via Inhibition of STAT3 Activation in MDA-MB-231 Cells

Hyunsook An; Ji Young Kim; Eunhye Oh; Nahyun Lee; Youngkwan Cho; Jae Hong Seo

doi:10.1371/journal.pone.0141919

Salinomycin Promotes Anoikis and Decreases the CD44+/CD24- Stem-Like Population via Inhibition of STAT3 Activation in MDA-MB-231 Cells

PLoS One. 2015 Nov 3;10(11):e0141919. doi: 10.1371/journal.pone.0141919. eCollection 2015.

Authors

Hyunsook An¹, Ji Young Kim¹, Eunhye Oh¹, Nahyun Lee¹, Youngkwan Cho¹, Jae Hong Seo¹

Affiliation

¹ Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea; Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive tumor subtype with an enriched CD44+/CD24- stem-like population. Salinomycin is an antibiotic that has been shown to target cancer stem cells (CSC); however, the mechanisms of action involved have not been well characterized. The objective of the present study was to investigate the effect of salinomycin on cell death, migration, and invasion, as well as CSC-like properties in MDA-MB-231 breast cancer cells. Salinomycin significantly induced anoikis-sensitivity, accompanied by caspase-3 and caspase-8 activation and PARP cleavage, during anchorage-independent growth. Salinomycin treatment also caused a marked suppression of cell migration and invasion with concomitant downregulation of MMP-9 and MMP-2 mRNA levels. Notably, salinomycin inhibited the formation of mammospheres and effectively reduced the CD44+/CD24- stem-like population during anchorage-independent growth. These observations were associated with the inhibition of STAT3 phosphorylation (Tyr705). Furthermore, interleukin-6 (IL-6)-induced STAT3 activation was strongly suppressed by salinomycin challenge. These findings support the notion that salinomycin may be potentially efficacious for targeting breast cancer stem-like cells through the inhibition of STAT3 activation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anoikis
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Cell Line, Tumor
Humans
Hyaluronan Receptors*
Interleukin-6 / genetics
Interleukin-6 / metabolism
Male
Matrix Metalloproteinase 2 / biosynthesis
Matrix Metalloproteinase 2 / genetics
Matrix Metalloproteinase 9 / biosynthesis
Matrix Metalloproteinase 9 / genetics
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Neoplastic Stem Cells / metabolism*
Neoplastic Stem Cells / pathology
Pyrans / pharmacology*
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism*
Sialic Acid Binding Ig-like Lectin 2*

Substances

Hyaluronan Receptors
IL6 protein, human
Interleukin-6
Neoplasm Proteins
Pyrans
STAT3 Transcription Factor
STAT3 protein, human
Sialic Acid Binding Ig-like Lectin 2
salinomycin
MMP2 protein, human
Matrix Metalloproteinase 2
MMP9 protein, human
Matrix Metalloproteinase 9

Grants and funding

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI12C1852). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.