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 language | English |
|---|---|
| Pages (from-to) | 719-731 |
| Number of pages | 13 |
| Journal | Neoplasia (United States) |
| Volume | 14 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Aug 2012 |
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ASJC Scopus subject areas
- Cancer Research
Cite this
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 journal › Article
}
TY - JOUR
T1 - 3-Phosphoinositide-dependent kinase 1 controls breast tumor growth in a kinase-dependent but Akt-independent manner
AU - Gagliardi, Paolo Armando
AU - di Blasio, Laura
AU - Orso, Francesca
AU - Seano, Giorgio
AU - Sessa, Roberto
AU - Taverna, Daniela
AU - Bussolino, Federico
AU - Primo, Luca
PY - 2012/8
Y1 - 2012/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84865202387&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84865202387&partnerID=8YFLogxK
U2 - 10.1593/neo.12856
DO - 10.1593/neo.12856
M3 - Article
C2 - 22952425
AN - SCOPUS:84865202387
VL - 14
SP - 719
EP - 731
JO - Neoplasia
JF - Neoplasia
SN - 1522-8002
IS - 8
ER -