Metastasis is responsible for most cancer deaths, including breast, lung or head and neck cancers. However, the molecular processes underlying cellular changes that promote tumor metastasis are still poorly understood. We found that p90 Ribosomal S6 kinase 2 (RSK2) is commonly important to promote multiple steps that comprise tumor metastasis, such as resistance to anoikis induction, cell migration and invasion, and tumor metastasis in metastatic human cancers including breast, lung, and head and neck cancers. Through incorporated phosphor-proteomics and genomics based studies, we demonstrated that RSK2 mediates anti-anoikis, pro-invasive and pro-metastatic signals by phosphorylating a spectrum of downstream factors. In particular, we identified novel substrates of RSK2, including apoptosis signal-regulating kinase 1 (ASK1) and IRS1, to provide anti-anoikis protection and promote pro-invasive and pro-metastatic potentials in cancer cells, respectively. Moreover, we demonstrated that RSK2-CREB signaling pathway regulate gene expression of a group of proteins that are involved in cell death regulation including pro-apoptotic ING3 to provide anti-anoikis protection, as well as proteins that promote epithelial-mesenchymal transition (EMT) including vitronectin (VTN). These factors intertwine with each other to form a signaling network, which mediates RSK2 signals to provide a pro-survival and pro-metastatic advantage to human cancers in both transcription-dependent and -independent manners. Furthermore, our preliminary studies showed that treatment with a novel, bio-available RSK specific inhibitor, FMK-MEA significantly attenuates cancer cell invasion and tumor metastasis. Thus, our central hypothesis is that RSK2 signaling pathway is commonly activated in metastatic cancers, which provides anti-anoikis protection and promotes cancer cell invasion and tumor metastasis in both transcription-dependent and -independent manners. RSK2 signaling represents an attractive anti-metastasis therapy in cancer treatment.
Three Specific Aims are proposed: (1) To determine whether RSK2 provides anti-anoikis protection to cancer cells by inhibiting a newly identified phosphorylation target ASK1 and downregulating CREB-dependent gene expression of pro-apoptotic protein ING3;(2) To determine whether RSK2 mediates pro-invasive and pro-migratory signals in cancer cells by phosphorylating pro-metastatic protein IRS1 and upregulating gene expression of EMT promoting effector VTN that is a RSK2-CREB transcription target;(3) To validate RSK2 and its signaling effectors in tumor specimens as therapeutic targets and treat human metastatic cancers in vitro and in vivo using a novel RSK inhibitor FMK-MEA in combination with anti-cancer agents including cisplatin.

Public Health Relevance

Metastasis is the leading cause of death in human patients with breast, lung or head and neck cancers, but however, the signaling and molecular mechanisms underlying metastases in these cancer types remain unclear. We found that p90 ribosomal S6 kinase 2 (RSK2) is commonly activated in diverse human cancer cells, which provides anti-anoikis protection and promotes cancer cell invasion and tumor metastasis. In this proposal, we will examine the role of RSK2 as a signal integrator in metastatic cells by phosphorylating and regulating multiple protein factors to provide anti-anoikis, pro-invasive and pro-metastatic signals in cancer cells, and validate RSK2 signaling pathways in combination with others as an alternative therapeutic target in treatment of metastatic cancers using a novel RSK inhibitor FMK-MEA.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA175316-01A1
Application #
8695575
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
2014-04-01
Project End
2019-02-28
Budget Start
2014-04-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$323,700
Indirect Cost
$116,200
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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