AKT1/PKBα Kinase Is Frequently Elevated in Human Cancers and Its Constitutive Activation Is Required for Oncogenic Transformation in NIH3T3 Cells

Abstract

Extensive studies have demonstrated that the Akt/AKT1 pathway is essential for cell survival and inhibition of apoptosis; however, alterations of Akt/AKT1 in human primary tumors have not been well documented. In this report, significantly increased AKT1 kinase activity was detected in primary carcinomas of prostate (16 of 30), breast (19 of 50), and ovary (11 of 28). The results were confirmed by Western blot and immunohistochemical staining analyses with phospho-Ser473 Akt antibody. The majority of AKT1-activated tumors are high grade and stage III/lV (13 of 16 prostate, 15 of 19 breast, and 8 of 11 ovarian carcinomas). Previous studies showed that wild-type AKT1 was unable to transform NIH3T3 cells. To demonstrate the biological significance of AKT1 activation in human cancer, constitutively activated AKT1 (Myr-Akt) was introduced into NIH3T3 cells. Overexpression of Myr-Akt in the stably transfected cells resulted in malignant phenotype, as determined by growth in soft agar and tumor formation in nude mice. These data indicate that AKT1 kinase, which is frequently activated in human cancer, is a determinant in oncogenesis and a potential target for cancer intervention.

Epithelial Stem Cells of the Prostate and Their Role in Cancer Progression

“…Alterations in the PTEN/AKT pathway are commonly seen in human prostate cancer as an activation of AKT or a loss of function in PTEN (Sun et al 2001;Deocampo et al 2003). Transgenic mice harboring a prostate-specific constitutively active AKT develop PIN lesions (Majumder et al 2003), whereas conditional PTEN null mice develop prostate cancers that progress in a step-like fashion, as in the human disease (Wang et al 2003;Ma et al 2005).…”

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

“…Akt gene amplification has been observed in prostate cancer 78,79 and other malignancies including ovarian cancer, 80,81 pancreatic cancer, 82 gastric cancer, 83 thyroid cancer, 84 and breast cancer. 80,85 Elevated Akt expression and kinase activities are associated with a hormone-resistant phenotype and correlates with a poor prognosis in human prostate cancer and breast cancer. 78,79,85,86 Upstream of Akt, amplification of PI3-K has been reported for prostate, 79 ovarian, 87,88 colon, 88 and breast cancer.…”

“…80,85 Elevated Akt expression and kinase activities are associated with a hormone-resistant phenotype and correlates with a poor prognosis in human prostate cancer and breast cancer. 78,79,85,86 Upstream of Akt, amplification of PI3-K has been reported for prostate, 79 ovarian, 87,88 colon, 88 and breast cancer. 85 Several protein-tyrosine kinases (PTKs), which act upstream of the PI3-K and are important regulators of the PI3-K-Akt pathway, have been found overexpressed in various cancers because of activating mutations or other genetic alterations.…”

“…78,79,85,86 Upstream of Akt, amplification of PI3-K has been reported for prostate, 79 ovarian, 87,88 colon, 88 and breast cancer. 85 Several protein-tyrosine kinases (PTKs), which act upstream of the PI3-K and are important regulators of the PI3-K-Akt pathway, have been found overexpressed in various cancers because of activating mutations or other genetic alterations. For example, FGFR1 is overexpressed in localized prostate cancer and amplified in hormone-resistant prostate cancers; 79 ErbB2/HER2/Neu is overexpressed in prostate, breast, ovarian, gastric, nonsmall lung and colon cancers; [89][90][91][92] IGF-1R expression A most striking discovery is the association of functional loss of PTEN with advanced human cancer, including prostate cancer.…”

PDK-1/AKT pathway as a novel therapeutic target in rhabdomyosarcoma cells using OSU-03012 compound

“…PDK-1 can transform normal human cells and may be involved in invasion and metastasis process (Zeng et al, 2002;Xie et al, 2003Xie et al, , 2006. PDK-1 and its downstream target AKT are frequently phosphorylated and activated in multiple types of cancers (Cheng et al, 1992;Sun et al, 2001;Lin et al, 2005). Constitutive activation of PI3-K/PDK-1/AKT signalling mediates the survival signals and confers resistance to apoptosis induced by anticancer cytotoxic agents in human cancer cells (Page et al, 2000;Nesterov et al, 2001;Clark et al, 2002).…”