Invasive growth of
glioblastoma makes
residual tumor unremovable by surgery and leads to disease relapse.
Temozolomide is widely used first-line
chemotherapy drug to treat
glioma patients, but development of
temozolomide resistance is almost inevitable. Ferroptosis, an
iron-dependent form of non-apoptotic cell death, is found to be related to
temozolomide response of
gliomas. However, whether inducing ferroptosis could affect invasive growth of
glioblastoma cells and which ferroptosis-related regulators were involved in
temozolomide resistance are still unclear. In this study, we treated
glioblastoma cells with RSL3, a ferroptosis inducer, in vitro (cell lines) and in vivo (subcutaneous and orthotopic animal models). The treated
glioblastoma cells with wild-type or mutant IDH1 were subjected to
RNA sequencing for transcriptomic profiling. We then analyze data from our
RNA sequencing and public TCGA
glioma database to identify ferroptosis-related
biomarkers for prediction of prognosis and
temozolomide resistance in
gliomas. Analysis of transcriptome data from RSL3-treated
glioblastoma cells suggested that RSL3 could inhibit
glioblastoma cell growth and suppress expression of genes involved in cell cycle. RSL3 effectively reduced mobility of
glioblastoma cells through downregulation of critical genes involved in epithelial-mesenchymal transition. Moreover, RSL3 in combination with
temozolomide showed suppressive efficacy on
glioblastoma cell growth, providing a promising therapeutic strategy for
glioblastoma treatment. Although
temozolomide attenuated invasion of
glioblastoma cells with mutant IDH1 more than those with wild-type IDH1, the combination of RSL3 and
temozolomide similarly impaired invasive ability of
glioblastoma cells in spite of IDH1 status. Finally, we noticed that both
ferritin heavy chain 1 and
ferritin light chain predicted unfavorable prognosis of
glioma patients and were significantly correlated with
mRNA levels of methylguanine
methyltransferase as well as
temozolomide resistance. Altogether, our study provided rationale for combination of RSL3 with
temozolomide to suppress
glioblastoma cells and revealed
ferritin heavy chain 1 and
ferritin light chain as
biomarkers to predict prognosis and
temozolomide resistance of
glioma patients.