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Signaling from mTOR to eIF2α mediates cell migration in response to the chemotherapeutic doxorubicin.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Harvey, Robert F 
Pöyry, Tuija AA 
Stoneley, Mark 
Willis, Anne E 

Abstract

After exposure to cytotoxic chemotherapeutics, tumor cells alter their translatome to promote cell survival programs through the regulation of eukaryotic initiation factor 4F (eIF4F) and ternary complex. Compounds that block mTOR signaling and eIF4F complex formation, such as rapamycin and its analogs, have been used in combination therapies to enhance cell killing, although their success has been limited. This is likely because the cross-talk between signaling pathways that coordinate eIF4F regulation with ternary complex formation after treatment with genotoxic therapeutics has not been fully explored. Here, we described a regulatory pathway downstream of p53 in which inhibition of mTOR after DNA damage promoted cross-talk signaling and led to eIF2α phosphorylation. We showed that eIF2α phosphorylation did not inhibit protein synthesis but was instead required for cell migration and that pharmacologically blocking this pathway with either ISRIB or trazodone limited cell migration. These results support the notion that therapeutic targeting of eIF2α signaling could restrict tumor cell metastasis and invasion and could be beneficial to subsets of patients with cancer.

Description

Keywords

Cell Line, Tumor, Cell Movement, Doxorubicin, Eukaryotic Initiation Factor-2, Humans, Phosphorylation, Signal Transduction, TOR Serine-Threonine Kinases, Tumor Suppressor Protein p53

Journal Title

Science Signaling

Conference Name

Journal ISSN

1937-9145
1937-9145

Volume Title

12

Publisher

American Association for the Advancement of Science

Rights

All rights reserved
Sponsorship
Wellcome Trust (110071/Z/15/Z)
R.F.H. was supported by MRC studentship and Wellcome Trust (grant number 110071/Z/15/Z). A.E.W., T.A.A.P., and M.S. were supported by MRC Programme funding (MC_UP_A600_1023)