Impairment of stress granule assembly via inhibition of the eIF2alpha phosphorylation sensitizes glioma cells to chemotherapeutic agents

Abstract

Malignant gliomas are a lethal type of brain tumors that poorly respond to chemotherapeutic drugs. Several therapy resistance mechanisms have been characterized. However, the response to stress through mRNA translational control has not been evaluated for this type of tumor. A potential target would involve the alpha subunit of eukaryotic translation initiation factor (eIF2α) that leads to assembly of stress granules (SG) which are cytoplasmic granules mainly composed by RNA binding proteins and untranslated mRNAs. We assessed whether glioma cells are capable of assembling SG after exposure to different classes of chemotherapeutic agents through evaluation of the effects of interfering in this process by impairing the eIF2α signaling. C6 and U87MG cells were exposed to bortezomib, cisplatin, or etoposide. Forced expression of a dominant negative mutant of eIF2α (eIF2α(DN)) was employed to block this pathway. We observed that exposure to drugs stimulated SG assembly. This was reduced in eIF2α(DN)-transfected cells and this strategy enhanced chemotherapeutically-induced cell death for all drugs. Our data suggest that SG assembly occurs in glioma cells in response to chemotherapeutic drugs in an eIF2α-dependent manner and this response is relevant for drug resistance. Interfering with eIF2α signaling pathway may be a potential strategy for new co-adjuvant therapies to treat gliomas.

TGF-β and NF-κB signaling pathway crosstalk potentiates corneal epithelial senescence through an RNA stress response

“…5B). The phosphorylation of the alpha subunit of eukaryotic translation initiation factor (eIF2α) is essential for SGs assembly [31]. We further measured the phosphorylation levels of eIF2α in HCECs treated with TGF-β, and found that it was much higher after TGF-β1 exposure (Fig.…”

A phase II trial evaluating the effects and intra-tumoral penetration of bortezomib in patients with recurrent malignant gliomas

“…One possibility is the TMZ dose was lower than other trials [11,12], others include increased resistance caused by the bortezomib prior surgery or less likely a drug interaction between TMZ and bortezomib. Bortezomib can induce resistance via eIF2alpha and that resistance is blocked by interfering with this signaling pathway [29]. Alternatively, it has been shown that bortezomib can sensitize glioma cells to an oncolytic herpes virus [30].…”

Anticancer metal drugs and immunogenic cell death

“…Accordingly, the eIF2α dephosphorylation inhibitor salubrinal (see Section 6) enhanced ROS production, ER stress and nephrotoxicity of cisplatin in a mouse model [61]. However, in sharp contrast, other studies reported eIF2α phosphorylation in response to cisplatin and a chemo-protective function of this effect in a glioma or a lung cancer background [62,63]. This suggests that cell-type dependent differences might exist.…”