Targeting the facilitative glucose transporter GLUT1 inhibits the self-renewal and tumor-initiating capacity of cancer stem cells

Abstract

Increased glucose metabolism is now recognized as an emerging hallmark of cancer. Recent studies have shown that glucose metabolism is even more active in cancer stem cells (CSCs), a rare population of cancer cells with the capacity to self-renew and initiate tumors, and that CSCs are dependent on glycolysis for their survival/growth. However, the role of glucose metabolism in the control of their self-renewal and tumor-initiating capacity per se still remains obscure. Moreover, much remains unknown as to which of the numerous molecules involved in the glucose metabolism is suitable as a target to control CSCs. Here we demonstrate that the facilitative glucose transporter GLUT1 is essential for the maintenance of pancreatic, ovarian, and glioblastoma CSCs. Notably, we found that WZB117, a specific GLUT1 inhibitor, could inhibit the self-renewal and tumor-initiating capacity of the CSCs without compromising their proliferative potential in vitro. In vivo, systemic WZB117 administration inhibited tumor initiation after implantation of CSCs without causing significant adverse events in host animals. Our findings indicate GLUT1-dependent glucose metabolism has a pivotal role not only in the growth and survival of CSCs but also in the maintenance of their stemness and suggest GLUT1 as a promising target for CSC-directed cancer therapy.

Cerebellar liponeurocytoma with atypical histological features – a rare example of a glioneuronal tumor

“…GLUT-1 expression is induced under hypoxic conditions. This phenomenon occurs in various types of malignancy including high-grade gliomas, where it mediates increased glucose uptake, being also associated with a worse clinical outcome [29]. Observed expression of GLUT-1 together with atypical histological features can support the higher histological grade in our case.…”

Inhibition of Glut1 by WZB117 sensitizes radioresistant breast cancer cells to irradiation

“…However, whether radiation induces glycolysis directly is still under investigate. Glut1 is a facilitative glucose transporter which belongs to the solute-linked carrier gene family SLC2, and the elevated expression of Glut1 has been documented in most cancers [13]. As an inhibitor of Glut1, WZB117 exhibits inhibitory action on cancer cell growth has been reported [12].…”

“…WZB117 is a small compound that has been reported to inhibit glucose transport and cell growth in several cancer cell lines through the down regulation of glucose transporter 1 (Glut1) [12][13][14]. Moreover, a recent study described inhibition of Glut1 could increase ROS levels of myoblasts, suggesting that inhibition of Glut1 might modulate the radiosensitivity through the increased ROS [15].…”

Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

“…Nowadays, several studies provide strong evidence for the existence of a cellular subpopulation with stem-like traits also in NSCLC [20,22,23], where the presence of these cells predicts a worse prognosis for patients [24]. Currently, the development of new treatment strategies that target CSCs, as well as the identification of new druggable pathways, are the main goals of anti-cancer therapy [25][26][27][28][29][30][31][32][33][34]. Commercially available established cancer cell lines cannot account for the genetic diversity among patients or for the heterogeneity of tumor cells.…”