Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten(-/-) melanoma.

Abstract

Phosphoinositide-dependent kinase-1 (PDK1) is a serine/threonine protein kinase that phosphorylates members of the conserved AGC kinase superfamily, including AKT and protein kinase C (PKC), and is implicated in important cellular processes including survival, metabolism and tumorigenesis. In large cohorts of nevi and melanoma samples, PDK1 expression was significantly higher in primary melanoma, compared with nevi, and was further increased in metastatic melanoma. PDK1 expression suffices for its activity, owing to auto-activation, or elevated phosphorylation by phosphoinositide 3'-OH-kinase (PI3K). Selective inactivation of Pdk1 in the melanocytes of Braf(V600E)::Pten(-/-) or Braf(V600E)::Cdkn2a(-/-)::Pten(-/-) mice delayed the development of pigmented lesions and melanoma induced by systemic or local administration of 4-hydroxytamoxifen. Melanoma invasion and metastasis were significantly reduced or completely prevented by Pdk1 deletion. Administration of the PDK1 inhibitor GSK2334470 (PDKi) effectively delayed melanomagenesis and metastasis in Braf(V600E)::Pten(-/-) mice. Pdk1(-/-) melanomas exhibit a marked decrease in the activity of AKT, P70S6K and PKC. Notably, PDKi was as effective in inhibiting AGC kinases and colony forming efficiency of melanoma with Pten wild-type (WT) genotypes. Gene expression analyses identified Pdk1-dependent changes in FOXO3a-regulated genes, and inhibition of FOXO3a restored proliferation and colony formation of Pdk1(-/-) melanoma cells. Our studies provide direct genetic evidence for the importance of PDK1, in part through FOXO3a-dependent pathway, in melanoma development and progression.

• Authors: M Scortegagna, C Ruller, Y Feng, R Lazova, H Kluger, J-L Li, S K De, R Rickert, M Pellecchia, M Bosenberg, Z A Ronai
• Journal: Oncogene (Oncogene) Vol. 33 Issue 34 Pg. 4330-9 (Aug 21 2014) ISSN: 1476-5594 [Electronic] England
• PMID: 24037523 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Forkhead Box Protein O3
• Forkhead Transcription Factors
• FoxO3 protein, mouse
• GSK 2334470
• Indazoles
• PDK1 protein, human
• Pdk1 protein, mouse
• Pyrimidines
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Braf protein, mouse
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins B-raf
• PTEN Phosphohydrolase
• Pten protein, mouse

Topics

• Animals
• Carcinogenesis (metabolism)
• Cell Line, Tumor
• Forkhead Box Protein O3
• Forkhead Transcription Factors (metabolism)
• Gene Knockout Techniques
• Humans
• Indazoles (pharmacology)
• Lung Neoplasms (enzymology, genetics, secondary)
• Lymphatic Metastasis
• Melanoma, Experimental (enzymology, genetics, secondary)
• Mice
• Mice, Knockout
• Mutation, Missense
• PTEN Phosphohydrolase (deficiency, genetics)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins B-raf (genetics, metabolism)
• Pyrimidines (pharmacology)
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Signal Transduction
• Skin Neoplasms (enzymology, genetics, pathology)
• Tissue Array Analysis