Nrf2 is required to maintain the self-renewal of glioma stem cells

Abstract

BackgroundGlioblastomas are deadly cancers that display a functional cellular hierarchy maintained by self-renewing glioma stem cells (GSCs). Self-renewal is a complex biological process necessary for maintaining the glioma stem cells. Nuclear factor rythroid 2-related factor 2(Nrf2) plays a significant role in protecting cells from endogenous and exogenous stresses. Nrf2 is a key nuclear transcription factor that regulates antioxidant response element (ARE)-containing genes. Previous studies have demonstrated the significant role of Nrf2 in the proliferation of glioblastoma, and in their resistance to radioactive therapies. We examined the effect of knocking down Nrf2 in GSCs.MethodsNrf2 expression was down-regulated by shRNA transinfected with lentivirus. Expression levels of Nestin, Nrf2, BMI-1, Sox2 and Cyclin E were assessed by western blotting, quantitative polymerase chain reaction (qPCR) and immunohistochemistry analysis. The capacity for self-renewal in vitro was assessed by genesis of colonies. The capacity for self-renewal in vivo was analyzed by tumor genesis of xenografts in nude mice.ResultsKnockdown of Nrf2 inhibited the proliferation of GSCs, and significantly reduced the expression of BMI-1, Sox2 and CyclinE. Knocking down of Nrf2 changed the cell cycle distribution of GSCs by causing an uncharacteristic increase in the proportion of cells in the G2 phase and a decrease in the proportion of cells in the S phase of the cell cycle.ConclusionsNrf2 is required to maintain the self-renewal of GSCs, and its down-regulation can attenuate the self-renewal of GSCs significantly.

Impact of nuclear factor erythroid-derived 2–like 2 and p62/sequestosome expression on prognosis of patients with gliomas

“…However, in response to cellular stress, Nrf2 isolates from Keap1, translocates to the nucleus, and up-regulates ARE-dependent gene expression [21]. These genes are related to a variety of proteins including antioxidant proteins, transport proteins, phase II detoxification enzymes, growth factors, proteasome subunits, drug-metabolizing enzymes, and multidrug-resistant protein-3 [5,[22][23][24]. Expression of these Nrf2-dependent proteins is crucial for survival and growth of cancer cells.…”

“…Berberat et al [26] reported that suppression of the Nrf2 target HO-1 using siRNA caused a decrease in proliferation and the increased sensitivity to gemcitabine in pancreatic cancer. In GBs, Nrf2 is required to maintain the self-renewal of glioma stem cells, and its down-regulation can inhibit tumor growth and invasiveness [5].…”

“…Nuclear erythroid 2-related factor 2 (Nrf2) is a leucine zipper protein that controls the transcription of several antioxidant response element (ARE)-containing genes [5]. These ARE-dependent genes encode antioxidants, phase II detoxifying enzymes, and drug transporters to maintain cellular homeostasis; protect against oxidative injury; and promote cell survival under stress [6].…”

BMI-1, a promising therapeutic target for human cancer

“…Zhu et al revealed that knockdown of Nrf2 inhibited the proliferation of glioma stem cells and significantly reduced the expression levels of BMI-1, Sox2 and cyclin E (70).…”

Promoting differentiation and survival of human c-kit+ cardiac progenitor cells ex vivo.

“…Nrf2 is a TF that efficiently combats oxidative stress and may thus be utilized to enhance stem cell survival [65].…”