Abstract
Resistance to chemotherapy drugs is a serious therapeutic problem and its underlying molecular mechanisms are complex. Stress granules (SGs), cytoplasmic ribonucleoprotein complexes assembled in cells exposed to stress, are implicated in various aspects of cancer cell metabolism and survival. SGs promote the survival of stressed cells by reprogramming gene expression and inhibiting pro-apoptotic signaling cascades. We show that the vinca alkaloid (VA) class of anti-neoplastic agents potently activates a SG-mediated stress response program. VAs inhibit translation initiation by simultaneous activation of eIF4E-BP1 and phosphorylation of eIF2α, causing polysome disassembly and SG assembly. VA-induced SGs contain canonical SG components but lack specific signaling molecules. Blocking VA-induced SG assembly by inactivating eIF4EBP1 or inhibiting eIF2α phosphorylation decreases cancer cell viability and promotes apoptosis. Our data describe previously unappreciated effects of VAs on cellular RNA metabolism and illuminate the roles of SGs in cancer cell survival.
Highlights
Tumor cells reside in inhospitable environments that select for cells that acquire adaptive mechanisms that promote their growth and survival
To determine whether certain chemotherapy drugs induce Stress granules (SGs) formation, we performed an unbiased screening by challenging osteosarcoma U2OS cells with a library of FDA-approved chemotherapy drugs (~25 compounds) using variable drug concentrations
We identified chemotherapy drugs targeting the microtubule network as potent inducers of SGs (Figure 1A and 1B)
Summary
Tumor cells reside in inhospitable environments that select for cells that acquire adaptive mechanisms that promote their growth and survival. Phosphorylation of eIF2α at serine 51 (S51) by one of four stress-activated eIF2α kinases (PKR, PERK, GCN2 and HRI) prevents ternary complex assembly and inhibits translation initiation. The second control point regulates the assembly of the eIF4F (i.e. eIF4E:eIF4G:eIF4A) complex, controlled by the PI3K-mTOR (mammalian target of rapamycin) kinase cascade. Stress-induced inactivation of mTOR leads to the activation of its down-stream target, eIF4E-binding protein (e.g. eIF4E-BP1 (4E-BP1)). Activated 4E-BP1 prevents the assembly of eIF4F leading to inhibition of translation initiation. Both pathways play complementary roles in the control of translation, they allow targeted translational control of specific mRNA subsets [1,2,3]
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