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

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posted on 2023-06-10, 00:55 authored by 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
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Oncogene

ISSN

0950-9232

Publisher

Springer Nature

Issue

10

Volume

40

Page range

1851-1867

Event location

England

Department affiliated with

  • Biochemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2021-09-10

First Open Access (FOA) Date

2021-09-10

First Compliant Deposit (FCD) Date

2021-09-10

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