Regulation of Cancer Stem Cell Metabolism by Secreted Frizzled-Related Protein 4 (sFRP4).

Abhijeet Deshmukh,Frank Arfuso,Arun Dharmarajan,Philip Newsholme

doi:10.3390/cancers10020040

Abstract

Tumours contain a small number of treatment-resistant cancer stem cells (CSCs), and it is through these that tumour regrowth originates at secondary sites, thus rendering CSCs an attractive target for treatment. Cancer cells adapt cellular metabolism for aggressive proliferation. Tumour cells use less efficient glycolysis for the production of ATP and increasing tumour mass, instead of oxidative phosphorylation (OXPHOS). CSCs show distinct metabolic shift and, depending on the cancer type, can be highly glycolytic or OXPHOS dependent. Since Wnt signalling promotes glycolysis and tumour growth, we investigated the effect of the Wnt antagonist secreted frizzled-related protein 4 (sFRP4) on CSC metabolism. We demonstrate that sFRP4 has a prominent role in basal glucose uptake in CSCs derived from breast and prostate tumour cell lines. We show that sFRP4 treatment on CSCs isolated with variable glucose content induces metabolic reprogramming by relocating metabolic flux to glycolysis or OXPHOS. Altogether, sFRP4 treatment compromises cell proliferation and critically affects cell survival mechanisms such as viability, glucose transporters, pyruvate conversion, mammalian target of rapamycin, and induces CSC apoptosis under conditions of variable glucose content. Our findings provide the feasibility of using sFRP4 to inhibit CSC survival in order to induce metabolic reprogramming in vivo.

Highlights

Accumulating evidence suggest that tumours of various tissue origins, including breast, prostate, and ovary contain a small sub-population of cells with stemness capacity, often referred to as cancer stem cells (CSCs) or tumour initiating cells [1,2,3,4]
We demonstrated that the CSC metabolic profile changes with increasing glucose content in culture medium, and Wnt signalling plays a key role in mediating glucose induced CSC survival
Extracellular metabolites with secreted frizzled-related protein 4 (sFRP4) treatment of CSCs: Changes in glutamine uptake and glutamate secretion in CSCs grown in culture medium with increasing glucose concentrations were glutamate secretion in CSCs grown in culture medium with increasing glucose concentrations were measured. (A,E) MDA231 CSCs; (B,F) MCF7 CSCs; (C,G) PC-3 CSCs; and (D,H) LnCap CSCs were measured. (A,E) MDA231 CSCs; (B,F) MCF7 CSCs; (C,G) PC-3 CSCs; and (D,H) LnCap CSCs were treated with sFRP4 for 24 h

Summary

Introduction

Accumulating evidence suggest that tumours of various tissue origins, including breast, prostate, and ovary contain a small sub-population of cells with stemness capacity, often referred to as cancer stem cells (CSCs) or tumour initiating cells [1,2,3,4]. Another study demonstrated that brain CSCs exhibit low mitochondrial respiratory activity and prefer a hypoxic environment to maintain their stemness [11]. Glioma stem cells (GSCs) were glycolysis driven and were intrinsically sensitive to the use of a glycolytic inhibitor [13]. Cancer cells prefer glycolysis for their ATP production, and CSCs appear to have higher glycolytic activity. The Warburg hypothesis is consistent with the CSCs’ dependency on glycolysis and switching on oxidative phosphorylation to facilitate cytosolic glycolysis [14,15]. Based on these observations that glucose is an essential nutrient

Methods

Results

Conclusion