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

Paolo Armando Gagliardi, Laura di Blasio, Francesca Orso, Giorgio Seano, Roberto Sessa, Daniela Taverna, Federico Bussolino, Luca Primo

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)719-731
Number of pages13
JournalNeoplasia (United States)
Volume14
Issue number8
DOIs
Publication statusPublished - Aug 2012

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3-Phosphoinositide-Dependent Protein Kinases
Phosphotransferases
Breast Neoplasms
Growth
Phosphatidylinositol 3-Kinase
Anoikis
Mutation
Phosphatidylinositols

ASJC Scopus subject areas

  • Cancer Research

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3-Phosphoinositide-dependent kinase 1 controls breast tumor growth in a kinase-dependent but Akt-independent manner. / Gagliardi, Paolo Armando; di Blasio, Laura; Orso, Francesca; Seano, Giorgio; Sessa, Roberto; Taverna, Daniela; Bussolino, Federico; Primo, Luca.

In: Neoplasia (United States), Vol. 14, No. 8, 08.2012, p. 719-731.

Research output: Contribution to journalArticle

Gagliardi, Paolo Armando ; di Blasio, Laura ; Orso, Francesca ; Seano, Giorgio ; Sessa, Roberto ; Taverna, Daniela ; Bussolino, Federico ; Primo, Luca. / 3-Phosphoinositide-dependent kinase 1 controls breast tumor growth in a kinase-dependent but Akt-independent manner. In: Neoplasia (United States). 2012 ; Vol. 14, No. 8. pp. 719-731.
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