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Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of BrafV600E::Pten–/– melanoma

Oncogene volume 33, pages 4330–4339 (2014)Cite this article

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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 BrafV600E::Pten–/– or BrafV600E::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 BrafV600E::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.

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Acknowledgements

This manuscript is dedicated in fond memory to Victor Fung, Ph.D., a former Program Officer at NCI and a former Scientific Review Officer of the Cancer Etiology study section of CSR, NIH, for his wisdom, compassion, integrity, his love of the sciences and the arts and his contributions to the career development of so many investigators during his own distinguished career. We thank Dario Alessi for providing the conditional Pdk1–/– mice, Vincent Hearing for the Tyrp1 antibody and Pedro Aza-Blanc for small interfering RNA library work. Support by NIH grants CA099961 (to ZR) and CA128814 (to ZR and MP) and a Melanoma Research Alliance grant (to ZR) is gratefully acknowledged.

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Authors and Affiliations

  1. Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA

    M Scortegagna, C Ruller, Y Feng, J-L Li, S K De, R Rickert, M Pellecchia & Z A Ronai

  2. Department of Dermatology, Medicine and Pathology, Yale University, New Haven, CT, USA

    R Lazova, H Kluger & M Bosenberg

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  1. M Scortegagna
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Correspondence to Z A Ronai.

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Scortegagna, M., Ruller, C., Feng, Y. et al. Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of BrafV600E::Pten–/– melanoma. Oncogene 33, 4330–4339 (2014). https://doi.org/10.1038/onc.2013.383

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