Oncogene: MNK1 and MNK2 enforce expression of E2F1, FOXM1, and WEE1 to drive soft tissue sarcoma
Abstract
Soft tissue sarcoma (STS) is a heterogeneous disease that arises from connective tissues. Clinical outcomes of patients with advanced tumors especially de-differentiated liposarcoma and uterine leiomyosarcoma remain 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 oncoproteins including E2F1, FOXM1, and WEE1. Moreover, a combination of ETC-168 and MCL1 inhibitor S63845 exerts a synergistic antiproliferative activity against STS cells. In summary, our study reveals the crucial roles of MNK1/2 and their downstream targets in STS tumorigenesis. Our data encourage the further clinical translation of MNK inhibitors for STS treatment.
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Since 2004, UT Health San Antonio, Greehey Children’s Cancer Research Institute’s (Greehey CCRI) mission has been to advance scientific knowledge relevant to childhood cancer, contribute to the understanding of its causes, and accelerate the translation of knowledge into novel therapies. Through discovery, development, and dissemination of new scientific knowledge, Greehey CCRI strives to have a national and global impact on childhood cancer. Our mission consists of three key areas — research, clinical, and education.
Stay connected with the Greehey CCRI on Facebook, Twitter, LinkedIn, and Instagram.
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Since 2004, UT Health San Antonio, Greehey Children’s Cancer Research Institute’s (Greehey CCRI) mission has been to advance scientific knowledge relevant to childhood cancer, contribute to understanding its causes, and accelerate the translation of knowledge into novel therapies. Greehey CCRI strives to have a national and global impact on childhood cancer by discovering, developing, and disseminating new scientific knowledge. Our mission consists of three key areas — research, clinical, and education.
Stay connected with the Greehey CCRI on Facebook, Twitter, LinkedIn, and Instagram.