MNK1 and MNK2 enforce expression of E2F1, FOXM1, and WEE1 to drive soft tissue sarcoma

Xin Yu Ke, Ye Chen, Valarie Yu Yan Tham, Ruby Yu Tong Lin, Pushkar Dakle, Kassoum Nacro, Mark Edward Puhaindran, Peter Houghton, Angela Pang, Victor Kwanmin Lee, Ling Wen Ding, Sigal Gery, Jeffrey Hill, Leilei Chen, Liang Xu, H. Phillip Koeffler

Research output: Contribution to journalArticlepeer-review

Abstract

Soft tissue sarcoma (STS) is a heterogeneous disease that arises from connective tissues. Clinical outcome of patients with advanced tumors especially de-differentiated liposarcoma and uterine leiomyosarcoma remains unsatisfactory, despite intensive treatment regimens including maximal surgical resection, radiation, and chemotherapy. MAP kinase-interacting serine/threonine-protein kinase 1 and 2 (MNK1/2) have been shown to contribute to oncogenic translation via phosphorylation of eukaryotic translation initiation factor 4E (eIF4E). However, little is known about the role of MNK1/2 and their downstream targets in STS. In this study, we show that depletion of either MNK1 or MNK2 suppresses cell viability, anchorage-independent growth, and tumorigenicity of STS cells. We also identify a compelling antiproliferative efficacy of a novel, selective MNK inhibitor ETC-168. Cellular responsiveness of STS cells to ETC-168 correlates positively with that of phosphorylated ribosomal protein S6 (RPS6). Mirroring MNK1/2 silencing, ETC-168 treatment strongly blocks eIF4E phosphorylation and represses expression of sarcoma-driving onco-proteins including E2F1, FOXM1, and WEE1. Moreover, combination of ETC-168 and MCL1 inhibitor S63845 exerts a synergistic antiproliferative activity against STS cells. In summary, our study reveals crucial roles of MNK1/2 and their downstream targets in STS tumorigenesis. Our data encourage further clinical translation of MNK inhibitors for STS treatment.

Original languageEnglish (US)
Pages (from-to)1851-1867
Number of pages17
JournalOncogene
Volume40
Issue number10
DOIs
StatePublished - Mar 10 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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