Research ArticleCancer

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

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Science Signaling  17 Dec 2019:
Vol. 12, Issue 612, eaaw6763
DOI: 10.1126/scisignal.aaw6763

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Moved by DNA damage

Doxorubicin is a commonly used therapeutic that kills cancer cells by inducing genotoxic stress. Harvey et al. found that, at clinically relevant doses, doxorubicin promoted cancer cell migration. Doxorubicin inhibited the multiprotein complex mTORC1, which led to the phosphorylation of the translation factor eIF2α. This phosphorylation event would normally be expected to inhibit protein synthesis, but instead, it led to increased migration of doxorubicin-treated cancer cells. Inhibiting eIF2α phosphorylation with an FDA-approved drug restricted doxorubicin-induced cell migration. These results suggest that although inhibiting mTORC1 may shut down protein synthesis in tumors, it may enhance metastasis in response to doxorubicin.

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.

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