PI3K/Akt signalling pathway and cancer

Vara, Juan Ángel Fresno; Casado, Enrique; Castro, Javier de; Cejas, Paloma; Belda-Iniesta, Cristóbal; González-Barón, Manuel

doi:10.1016/j.ctrv.2003.07.007

Cited by 2,013 publications

(1,378 citation statements)

References 75 publications

Supporting

Mentioning

1,339

Contrasting

Unclassified

Order By: Relevance

“…PI3K is a major signalling component downstream of growth factor receptor tyrosine kinase, and the PI3K pathway regulates various cellular processes, such as proliferation, growth, apoptosis and cytoskeleton rearrangement (Cantley, 2002). The aberrant activation of the PI3K pathway has been widely implicated in several types of carcinomas (Vivanco and Sawyers, 2002;Fresno Vara et al, 2004). In our in vitro study, the PI3K activity was assessed at higher level in TE8, TE9 and TE10 than in TE1 and TE11.…”

Section: Discussionmentioning

confidence: 89%

Laminin-332 promotes the invasion of oesophageal squamous cell carcinoma via PI3K activation

et al. 2008

View full text Add to dashboard Cite

Laminin-332 is major component of epithelial basement membrane, and has an important role in cell migration and tumour invasion. Recently, the phosphatidylinositol 3-kinase (PI3K) activation induced by laminin-332 during carcinogenesis or tumour invasion has been highlighted in skin squamous cell carcinoma. The expression of laminin-332 in 126 resected oesophageal squamous cell carcinoma (ESCC) specimens was immunohistochemically examined to determine its associations with the clinicopathological characteristics, and the effect of laminin-332 on the invasiveness and the PI3K activation was assessed by in vitro experiments using ESCC cell lines (ESCCs). Sections with immunostaining signals in 430% cancer cells, which were observed in 55 of 126 cases, were judged to be positive for laminin-332. The positivity was significantly correlated with pTNM stage and poor prognosis. Inactivation of the PI3K pathway by laminin-332 blocking antibody suppressed the invasiveness of TE8 cell line, which secreted laminin-332 at high level and had high PI3K activity. The addition of the purified laminin-332 activated the PI3K pathway and increased the invasiveness of TE11 cell line, which secreted laminin-332 at lower level and had low PI3K activity. The deactivation of PI3K pathway using the PI3K inhibitor decreased the invasiveness of ESCCs and the secretion of laminin-332 in vitro. The expression of laminin-332 was one of the prognostic factors of ESCC. Laminin-332 could provide the autocrine positive-feedback loop through PI3K activation, contributing the invasive ability. Therefore, the inhibitor of PI3K pathway might be useful as the anticancer therapies for ESCC.

show abstract

Section: Discussionmentioning

confidence: 89%

Laminin-332 promotes the invasion of oesophageal squamous cell carcinoma via PI3K activation

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Often such genetic alterations result in constitutive activation of common downstream signal transduction pathways such as the mitogen-activated protein (MAP) kinase cascades of several serine/threonine kinases, including Raf-1, Mek-1, extracellular signal-regulated kinase (Erk)1/2, p38 and Jun kinase (JNK) (Hagemann and Blank, 2001;Johnson and Lapadat, 2002). Other pathways involved in uncontrolled proliferation, apoptosis, invasion and angiogenesis also include those mediated by the signal transducer and activator of transcription STAT3 and the serine/threonine kinase Akt (Alvarez and Frank, 2004;Fresno Vara et al, 2004). Not only have these oncogenic and tumor survival pathways been found constitutively activated in the great majority of human cancers, but also their hyperactivation has been associated with poor prognosis and resistance to chemotherapy in cancer patients (Slamon et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

A chemical biology approach identifies a beta-2 adrenergic receptor agonist that causes human tumor regression by blocking the Raf-1/Mek-1/Erk1/2 pathway

Carie

Sebti

2007

Oncogene

View full text Add to dashboard Cite

A chemical biology approach identifies a beta 2 adrenergic receptor (b2AR) agonist ARA-211 (Pirbuterol), which causes apoptosis and human tumor regression in animal models. b2AR stimulation of cAMP formation and protein kinase A (PKA) activation leads to Raf-1 (but not B-Raf) kinase inactivation, inhibition of Mek-1 kinase and decreased phospho-extracellular signal-regulated kinase (Erk)1/2 levels. ARA-211 inhibition of the Raf/ Mek/Erk1/2 pathway is mediated by PKA and not exchange protein activated by cAMP (EPAC). ARA-211 is selective and suppresses P-Erk1/2 but not P-JNK, P-p38, P-Akt or P-STAT3 levels. b2AR stimulation results in inhibition of anchorage-dependent and -independent growth, induction of apoptosis in vitro and tumor regression in vivo. b2AR antagonists and constitutively active Mek-1 rescue from the effects of ARA-211, demonstrating that b2AR stimulation and Mek kinase inhibition are required for ARA-211 antitumor activity. Furthermore, suppression of growth occurs only in human tumors where ARA-211 induces cAMP formation and decreases P-Erk1/2 levels. Thus, b2AR stimulation results in significant suppression of malignant transformation in cancers where it blocks the Raf-1/Mek-1/Erk1/2 pathway by a cAMP-dependent activation of PKA but not EPAC.

show abstract

“…Akt is a serine-threonine kinase involved in metabolism, proliferation, motility and survival (Fresno Vara et al, 2004). Regulation of Akt requires the participation of several different proteins.…”

Section: Introductionmentioning

confidence: 99%

Akt activation by arachidonic acid metabolism occurs via oxidation and inactivation of PTEN tumor suppressor

2007

View full text Add to dashboard Cite

Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzymes are overexpressed during inflammation and multistage tumor progression in many neoplastic disorders including lung, breast and pancreatic cancers. Here we report that the tumor suppressor phosphatase and tensin homolog (PTEN) is oxidized and inactivated during arachidonic acid (AA) metabolism in pancreatic cancer cell lines expressing COX-2 or 5-LOX. Oxidation of PTEN decreases its phosphatase activity, favoring increased phosphatidylinositol 3,4,5-triphosphate production, activation of Akt and phosphorylation of downstream Akt targets including GSK-3b and S6K. These effects are recapitulated with pancreatic phospholipase A 2 , which hydrolyses the release of membrane-bound AA. Interference with PTEN's physiological antagonism of signals from growth factors, insulin and oncogenes may confer risk for hypertrophic or neoplastic diseases associated with chronic inflammation or unwarranted oxidative metabolism of essential fatty acids.

show abstract

PI3K/Akt signalling pathway and cancer

Cited by 2,013 publications

References 75 publications

Laminin-332 promotes the invasion of oesophageal squamous cell carcinoma via PI3K activation

Laminin-332 promotes the invasion of oesophageal squamous cell carcinoma via PI3K activation

A chemical biology approach identifies a beta-2 adrenergic receptor agonist that causes human tumor regression by blocking the Raf-1/Mek-1/Erk1/2 pathway

Akt activation by arachidonic acid metabolism occurs via oxidation and inactivation of PTEN tumor suppressor

Contact Info

Product

Resources

About