3-phosphoinositide-dependent kinase 1 controls breast tumor growth in a kinase-dependent but Akt-independent manner

Neoplasia. 2012 Aug;14(8):719-31. doi: 10.1593/neo.12856.

Abstract

3-phosphoinositide-dependent protein kinase 1 (PDK1) is the pivotal element of the phosphatidylinositol 3 kinase (PI3K) signaling pathway because it phosphorylates Akt/PKB through interactions with phosphatidylinositol 3,4,5 phosphate. Recent data indicate that PDK1 is overexpressed in many breast carcinomas and that alterations of PDK1 are critical in the context of oncogenic PI3K activation. However, the role of PDK1 in tumor progression is still controversial. Here, we show that PDK1 is required for anchorage-independent and xenograft growth of breast cancer cells harboring either PI3KCA or KRAS mutations. In fact, PDK1 silencing leads to increased anoikis, reduced soft agar growth, and pronounced apoptosis inside tumors. Interestingly, these phenotypes are reverted by PDK1 wild-type but not kinase-dead mutant, suggesting a relevant role of PDK1 kinase activity, even if PDK1 is not relevant for Akt activation here. Indeed, the expression of constitutively active forms of Akt in PDK1 knockdown cells is unable to rescue the anchorage-independent growth. In addition, Akt down-regulation and pharmacological inhibition do not inhibit the effects of PDK1 overexpression. In summary, these results suggest that PDK1 may contribute to breast cancer, even in the absence of PI3K oncogenic mutations and through both Akt-dependent and Akt-independent mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Animals
  • Anoikis / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Proliferation
  • Cell Survival / genetics
  • Chromones / pharmacology
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Morpholines / pharmacology
  • Mutation
  • Nuclear Proteins / genetics
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins p21(ras)
  • Pyrazoles / pharmacology
  • RNA Interference
  • RNA, Small Interfering
  • Signal Transduction / genetics
  • Sulfonamides / pharmacology
  • Transcription Factors / genetics
  • Transplantation, Heterologous
  • ras Proteins / genetics

Substances

  • Chromones
  • KRAS protein, human
  • Morpholines
  • Nuclear Proteins
  • OSU 03012
  • PI3KCA protein, human
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pyrazoles
  • RNA, Small Interfering
  • Sulfonamides
  • Transcription Factors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinase
  • 3-Phosphoinositide-Dependent Protein Kinases
  • PDPK1 protein, human
  • Pdpk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins