Oncogenic PI3K deregulates transcription and translation

Bader, Andreas G.; Kang, Sohye; Zhao, Li; Vogt, Peter K.

doi:10.1038/nrc1753

Cited by 709 publications

(619 citation statements)

References 163 publications

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“…It has been shown that p110b possesses both lipid and protein kinase activities (reviewed in Bader et al, 2005;Engelman et al, 2006). To determine which activity of p110b kinase is involved in AR transactivation, we tested the effect of different p110b mutants, a total kinase-dead mutant (K805R) and a protein kinase only mutant (PKO, lipid kinase deficient) on Figure 1 Phosphoinositide 3-OH kinases (PI3K) p85a and p110b isoforms are essential for androgen-induced androgen receptor (AR) transactivation and cell proliferation.…”

Section: Resultsmentioning

confidence: 99%

“…Phosphoinositide 3-OH kinases (PI3Ks) regulate multiple cellular signal pathways (reviewed in Bader et al, 2005;Engelman et al, 2006). In mammalian cells, there are three classes (I, II and III) of PI3K isoforms, and the class I PI3Ks are further divided into two subtypes (IA p110 a/b/d and IB p110g), of which IA catalytic isoforms are associated with p85 regulatory subfamily, while IB p110g is associated with p101/p84 regulatory subunit.…”

Section: Introductionmentioning

confidence: 99%

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Phosphoinositide 3-OH kinase p85α and p110β are essential for androgen receptor transactivation and tumor progression in prostate cancers

et al. 2008

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Phosphoinositide 3-OH kinases (PI3Ks) are a group of major intracellular signaling molecules. In our previous study, we found that inhibition of PI3K activity suppressed the androgen receptor (AR)-mediated gene expression in prostate cancer cells. The AR has been considered as a critical determinant for the development and progression of human prostate cancers. In this study, we sought to identify the PI3K isoforms involved in AR transactivation. Using a gene-specific small interference RNA (siRNA) approach, we determined that the regulatory isoform p85a and the catalytic isoform p110b, but not p110a, were required for androgen-stimulated AR transactivation and cell proliferation in prostate cancer cells. Consistently, overexpression of wild-type p110b but not p110a gene led to androgen-independent AR transactivation. Silencing p110b gene in prostate cancer cells abolished tumor growth in nude mice. Of the dual (lipid and protein) kinase activities, p110b's lipid kinase activity was required for AR transactivation. Further analysis by a chromatin immunoprecipitation assay showed that p110b is indispensable for androgen-induced AR-DNA interaction. Finally, gene expression analysis of clinical specimens showed that both p85a and p110b were highly expressed in malignant prostate tissues compared to the nonmalignant compartments, and their expression levels correlated significantly with disease progression. Taken together, our data demonstrated that p85a and p110b are essential for androgen-stimulated AR transactivation, and their aberrant expression or activation might play an important role in prostate cancer progression.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phosphoinositide 3-OH kinase p85α and p110β are essential for androgen receptor transactivation and tumor progression in prostate cancers

et al. 2008

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“…The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is activated in multiple cancers, leading to oncogenic transformation (Vivanco and Sawyers, 2002;Bader et al, 2005;Wymann and Marone, 2005). Activation may result from activating mutations in PI3-kinase genes or inactivating mutations in the tumor suppressor gene PTEN (phosphatase and tensin homolog).…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

Abubaker¹,

Bavi²,

Al-harbi³

et al. 2008

Oncogene

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Activation of the phosphatidylinositol 3 0 -kinase (PI3K)/ AKT pathway results in an increase in cell proliferation and survival. Somatic mutations within the PI3K catalytic subunit, PIK3CA are common cause of increasing PI3K activity and are believed to be oncogenic in many cancer types. Few reports addressed the association between PIK3CA mutations and tumor progression specifically in microsatellite instable (MSI) colorectal cancer (CRC). In the present study, we have evaluated PIK3CA mutational status in a series of 410 Middle Eastern CRC and 13 colon cell lines to study the prevalence of PIK3CA mutations in MSI cases, PTEN expression in CRC and possibility of therapeutic targeting of this set of patients. PIK3CA mutations were found in four of the cell lines tested and 51 colorectal carcinomas (12.2%). Three of these four mutated cell lines were MSI. PTEN was inactivated in 66.1% of the CRC. Furthermore, we observed a strong association between PIK3CA mutations and MSI status (P ¼ 0.0046) while PTEN loss was more frequent in microsatellite stable (MSS) CRC (P ¼ 0.043). A high prevalence of genetic alterations in PI3K/AKT pathway in Saudi cohort of CRC, predominance of PIK3CA mutations in the MSI subgroup and their possible involvement in development/progression of this subset of CRC are some of the significant findings of our study.

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“…2,6 The RAS-MAPK and PI3K-AKT pathways are strongly interconnected and have a central role in tumorigenesis. RAS is activated by growth factors and hormone signaling, binding to RAF proteins (also named MAPKKKs).…”

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confidence: 99%

PI3K signaling pathway is activated by PIK3CA mRNA overexpression and copy gain in prostate tumors, but PIK3CA, BRAF, KRAS and AKT1 mutations are infrequent events

et al. 2011

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The phosphatidylinositol 3-kinase (PI3K)-AKT and RAS-MAPK pathways are deregulated in a wide range of human cancers by gain or loss of function in several of their components. Our purpose has been to identify genetic alterations in members of these pathways in prostate cancer. A total of 102 prostate tumors, 79 from prostate cancer alone (group G1) and 23 from bladder and prostate cancer patients (G2), are the subject of this study. In 20 of these 23, the bladder tumors were also analyzed. PIK3CA, KRAS, BRAF and AKT1 mutations were analyzed by direct sequencing, and BRAF also by pyrosequencing. PIK3CA quantitative mRNA expression and fluorescence in situ hybridization (FISH) gains were tested in 25 and 32 prostate tumors from both groups (G1 and G2), respectively. Immunohistochemistry for pAKT was performed in 55 prostate tumors. Of 25 prostate tumors, 10 (40%) had PIK3CA mRNA overexpression that was statistically associated with Gleason score Z7 (P ¼ 0.018). PIK3CA copy gain was detected in 9 of 32 (28%) prostate tumors. Of 20 bladder tumors, 3 (15%) displayed mutations in PIK3CA, KRAS and AKT1, the corresponding prostate tumors being wt. We also detected a previously not reported PIK3CA polymorphism (IVS9 þ 91) in two prostate tumors. In all, 56% of prostate tumors overexpressed pAKT. There is a statistical association (Po0.0001) of strong pAKT immunostaining with high Gleason score, and with PIK3CA alterations (mRNA overexpression and/or FISH gains). PIK3CA gene is deregulated by mRNA overexpression and DNA gain in B40 and 28% of prostate tumors, respectively. High-grade prostate tumors are associated with PIK3CA mRNA overexpression, but not with FISH status. PIK3CA, BRAF, KRAS and AKT1 mutations are very infrequent events in prostate tumors. However, PI3K signaling pathway is activated by PIK3CA FISH gain and/or mRNA overexpression, leading to an increased pAKT protein expression.

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Oncogenic PI3K deregulates transcription and translation

Cited by 709 publications

References 163 publications

Phosphoinositide 3-OH kinase p85α and p110β are essential for androgen receptor transactivation and tumor progression in prostate cancers

Phosphoinositide 3-OH kinase p85α and p110β are essential for androgen receptor transactivation and tumor progression in prostate cancers

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

PI3K signaling pathway is activated by PIK3CA mRNA overexpression and copy gain in prostate tumors, but PIK3CA, BRAF, KRAS and AKT1 mutations are infrequent events

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