Metastasis is responsible for most cancer deaths, including breast cancer, lung cancer or head and neck cancer. 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 cancer, lung cancer, and head and neck cancer. 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 cancer, lung cancer or head and neck cancer, 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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Jin, L; Chun, J; Pan, C et al. (2017) Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis. Oncogene 36:3797-3806
Jin, L; Alesi, G N; Kang, S (2016) Glutaminolysis as a target for cancer therapy. Oncogene 35:3619-25
Fan, Jun; Lin, Ruiting; Xia, Siyuan et al. (2016) Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth. Mol Cell 64:859-874
Alesi, G N; Jin, L; Li, D et al. (2016) RSK2 signals through stathmin to promote microtubule dynamics and tumor metastasis. Oncogene 35:5412-5421
Lin, Ruiting; Elf, Shannon; Shan, Changliang et al. (2015) 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling. Nat Cell Biol 17:1484-96
Jin, Lingtao; Li, Dan; Alesi, Gina N et al. (2015) Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell 27:257-70
Kang, Hee-Bum; Fan, Jun; Lin, Ruiting et al. (2015) Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling. Mol Cell 59:345-358
Shan, Changliang; Elf, Shannon; Ji, Quanjiang et al. (2014) Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth. Mol Cell 55:552-65
Fan, Jun; Kang, Hee-Bum; Shan, Changliang et al. (2014) Tyr-301 phosphorylation inhibits pyruvate dehydrogenase by blocking substrate binding and promotes the Warburg effect. J Biol Chem 289:26533-41
Jin, Lingtao; Li, Dan; Lee, Jong Seok et al. (2013) p90 RSK2 mediates antianoikis signals by both transcription-dependent and -independent mechanisms. Mol Cell Biol 33:2574-85

Showing the most recent 10 out of 11 publications