FDFT1 maintains glioblastoma stem cells through activation of the Akt pathway

Abstract

Background Cancer stem cells (CSCs) have unique metabolic characteristics and are hypothesized to contribute significantly to the recurrence and drug resistance of glioblastoma multiforme (GBM). However, the reliance on mitochondrial metabolism and the underlying mechanism of glioblastoma stem cells (GSCs) remains to be elucidated. Methods To quantify differential mitochondrial protein expression between GSCs and differentiated cells, a mass spectrum screen was applied by the Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC) technique. Functional experiments including CCK8, neurosphere formation, flow cytometry, transwell, and wound healing assays were conducted to evaluate GBM cell malignant phenotype. The potential molecular mechanism of FDFT1 was screened by RNA-seq analyses. The candidate target genes were validated through RT-qPCR and western blot analyses. Results As a top candidate, FDFT1 protein expression in GSCs was elevated relative to their differentiated counterparts. Functionally, the knockdown of FDFT1 suppressed the GBM cell proliferation and migration, while simultaneously enhancing sensitivity to temozolomide. Treatment with both the FDFT1 inhibitor (YM-53601) and simvastatin (an HMG-CoA reductase inhibitor) induced apoptosis in GSCs. Mechanistically, FDFT1 was transcriptionally regulated by SREBP2 but not SREBP1. Furthermore, FDFT1 activates the AKT pathway to regulate tumor metabolism and maintain the stemness of tumor cells. Conclusions GSCs exhibit a dependency on FDFT1-mediated mevalonate metabolism. Inhibition of FDFT1 could represent a potent strategy to eliminate GSCs.

1. Introduction

Glioblastoma multiforme (GBM), classified as a World Health Organization (WHO) grade IV astrocytoma, is one of the most prevalent tumors of the central nervous system. GBM is characterized by rapid cell proliferation, high malignancy, pronounced invasiveness, and a high mortality rate [1]. Although immunotherapy centered on immune checkpoint inhibitors has revolutionized the landscape of cancer treatment in recent years, its impact on neurological malignancies has been less pronounced [2, 3]. The primary approach to treating glioblastoma still relies on a conventional combination of surgical resection, radiotherapy, and chemotherapy.

Previous research has established that glioblastoma stem cells (GSCs) possess resistance to standard chemotherapeutic agents such as carmustine (bis-chloroethylnitrosourea, BCNU) and temozolomide (TMZ), along with radiation therapy [4, 5]. Given that GSCs may drive the recurrence of GBM [6, 7], there is an urgent need to further uncover the mechanisms of GSCs in recurrence and metastasis, thereby providing a convincing strategy for the development of targeted therapies against these cells to combat this highly aggressive form of cancer.

Abnormal metabolic state is considered as one of the biological characteristics of cancer stem cells. As the critical hub of cellular metabolism, mitochondrial metabolism is the essential condition that determines the fate of stem cells [8]. Our previous studies revealed that glioblastoma stem cells exhibit an altered mitochondrial metabolism compared to differentiated tumor cells [9–11]. These stem cells rely on aerobic glycolysis, or the Warburg effect, to generate energy in the absence of oxygen, a phenomenon commonly observed in cancer cells.