Holothuria scabra Extract Induces Cell Apoptosis and Suppresses Warburg Effect by Down-Regulating Akt/mTOR/HIF-1 Axis in MDA-MB-231 Breast Cancer Cells

Abstract

Introduction

Cancer cells utilize the modified glucose metabolism known as Warburg effect, with lactate production as the end product. In the search for alternative therapy, the body wall of sea cucumbers contains various substances with pharmacological activities. Herein, we investigate the effect of Holothuria scabra extract on the viability and Warburg effect of aggressive breast cancer cells.

Methods

Body wall of H. scabra was extracted using 95% ethanol. Triple-negative breast cancer cells, MDA-MB-231, were treated with the extract at various concentrations under normoglycemic and hyperglycemic conditions. Cytotoxicity test was performed using MTT assay. Apoptotic proteins were quantified using Western blot. Apoptotic cells were stained with Hoechst 33342. Lactate production was determined using L-lactate assay kit.

Results

By MTT assay, H. scabra extract suppressed the viability of breast cancer cells in a dose-dependent and time-dependent manner by enhancing apoptosis, indicated by a marked increase of proapoptotic Bax and pro-caspase three expressions, and decreased expression of anti-apoptotic Bcl-2. The extract could reduce hexokinase II expression, leading to reduced lactate production by blocking the Akt/mTOR/HIF-1 axis.

Discussion

Overall findings indicated that H. scabra extract could be a possible therapeutic against breast cancer progression in patients with hyperglycemia, for instance, diabetes mellitus.

Acknowledgments

The authors would like to thank the Agricultural Research Development Agency (Public Organization), Thailand, Prof. Prasert Sobhon, the Coastal Fisheries Research and Development Center, Prachuap Khiri Khan for the supplies of sea cucumbers, Research Fund, and the Central Instrument Facility (CIF) Grant, Faculty of Science, Mahidol University, Bangkok, Thailand.

Disclosure Statement

No potential conflict of interest was reported by the authors.

Authors’ Contributions

LY and KC conceived and designed the experiments. LY and KP performed the experiments. LY, SA, and KC wrote the manuscript. LY, SA, KP, and KC analyzed the data. LY, SA, KP, PS, and KC approved the final version of the manuscript.

Consent for Publication

All authors have read and approved the manuscript before publication.

Additional information

Funding

This work was supported by Agricultural Research Development Agency, Thailand, and the Central Instrument Facility Grant, Faculty of Science, Mahidol University.