Understanding the roles of stress granule during chemotherapy for patients with malignant tumors

Abstract

The assembly of stress granules (SGs) is a conserved mechanism to regulate protein synthesis under cell stress, where the translation of global protein is silenced and selective protein synthesis for survival maintains. SG formation confers survival advantages and chemotherapeutic resistance to malignant cells. Targeting SG assembly may represent a potential treatment strategy to overcome the primary and acquired chemotherapeutic resistance and enhance curative effect. We conduct a comprehensive review of the published literatures focusing on the drugs that potentially induce SGs and the related mechanism, retrospect the relationship between SGs and drug resistance related proteins, illuminate the regulated pathways and potential targets for SG assembly, and discuss future directions of overcoming the resistance to chemotherapy.

Keywords: G3BP1; Stress granule; chemoresistance; chemotherapy; mTOR signaling.

Figure 1

The assembly of stress granules in the phosphorylation of eIF2α dependent manner. Under steady-state conditions, eIF2/tRNA_i ^Met/GTP ternary complex can bind initiator tRNA_i ^Met to the 40S ribosomal subunit in a GTP-dependent manner. Adverse conditions activate the eIF2α kinases (HRI, PKR, PERK and GCN2) and lead to phosphorylation of eIF2α, which damage the ternary complex and impair translational initiation, following the formation of SGs. SGs are assemblies of untranslating messenger ribonucleoproteins that form from mRNAs stalled in translation initiation, also containing RNA-binding proteins, translation initiation factors, poly-A-binding protein and 40S ribosomal subunits.

Figure 2

Stress granules can be induced by chemotherapy drugs. Platinum induce reactive oxygen species and lead to SGs assembly. PKR protein can be activated by 5-Fluorouracil, inducing phosphorylation of eIF2α and cell death by apoptosis. Arsenic trioxide, vinorelbine and bortezomib can cause phosphorylation of eIF2α by activating PKR, PERK and HRI respectively.

Figure 3

The different roles of mTOR signaling in stress granules assembly. A. The activation of mTOR-S6 kinase pathway facilitates malignant progression of malignant tumor, and also promotes SGs assembly. The mTOR-S6 kinase pathway can promote SG assembly in response to mild oxidative stress by eIF2α phosphorylation, and mTOR/4EBP1/eIF4E axis enhances the ability of SGs assembly. B. mTORC1 is a main activator of translation, and thus translation arrest through mTORC1 inhibition may has potential to induce SGs assembly.

Figure 4

Targeting stress granules assembly may influence the efficacy of chemotherapy drugs. Targeting SG-nucleating proteins, eIF2α and its kinases, other eukaryotic translation initiation factors, and mTOR signaling may influence the SGs formation and the efficacy of chemotherapy drugs.