AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis

Roy, Hemant K.; Olusola, Bola F.; Clemens, Dahn L.; Karolski, William J.; Ratashak, Anne; Lynch, Henry T.; Smyrk, Thomas C.

doi:10.1093/carcin/23.1.201

Cited by 313 publications

(227 citation statements)

References 27 publications

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“…The effects of PI-3K on tumor growth and progression are thought to be mediated by Akt [64]. Akt is overexpressed in several cancers, including those of the colon, pancreas, ovary, and breast [65]. Moreover, Akt phosphorylation in human colon carcinomas correlates with cell proliferation and inhibition of apoptosis, as well as different clinicopathological parameters such as invasive grade, vessel infiltration, lymph node metastasis, and tumor stage [66,67].…”

Section: Discussionmentioning

confidence: 99%

Increased cell survival, migration, invasion, and Akt expression in PTHrP-overexpressing LoVo colon cancer cell lines

Shen¹,

Mula²,

Evers³

et al. 2007

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Parathyroid hormone-related protein (PTHrP) has been localized in human colon cancer tissue and cell lines. We have previously shown that PTHrP increases colon cancer cell proliferation, extracellular matrix adhesion, and cell-surface integrin α6β4 expression. Since cancer cell migration, invasion, and survival are crucial components of metastasis, and colon cancer has a high metastatic potential, in this study we used the human colon cancer cell line LoVo as a model system to study the effects of PTHrP on these parameters. PTHrP expression was modulated by stable transfection with a construct expressing PTHrP (−36 to +139). We report that PTHrP increases cell migration, invasion, and survival. PTHrP altered cell morphology, with PTHrP-overexpressing cells exhibiting increased spreading and several long protrusions. PTHrP also increased the steady-state mRNA levels of the integrin α6 and β4 subunits, indicating a direct and/or indirect effect of PTHrP on the transcriptional and/or posttranscriptional regulation of integrin α6 and β4 expression. Integrin α6β4 activates the phosphoinositol 3-kinase (PI3-K)/Akt pathway, leading to glycogen synthase kinase-3 (GSK-3) deactivation. PTHrP overexpression also led to an increase in active Akt and inactive GSK-3 levels, indicating that the PTHrP-mediated upregulation of integrin α6β4 expression may activate the PI3-K pathway, resulting in increased cell survival, migration and invasion.

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Section: Discussionmentioning

confidence: 99%

Increased cell survival, migration, invasion, and Akt expression in PTHrP-overexpressing LoVo colon cancer cell lines

Shen¹,

Mula²,

Evers³

et al. 2007

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“…Both the primary and metastatic neoplasm were considered positive when more than 1% of the tumour cells had score 2 and/or 3 (Roy et al, 2002).…”

Section: Evaluation Of Phospho-akt (Ser473) Expressionmentioning

confidence: 99%

Epidermal growth factor receptor (EGFR) downstream signalling pathway in primary colorectal tumours and related metastatic sites: optimising EGFR-targeted treatment options

et al. 2007

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We analysed the expression of activated (phosphorylated) Akt and MAPK in 98 cases of paired primary colorectal tumours and metastases with the aim to define better the epidermal growth factor receptor (EGFR)-related molecular profile of colorectal cancer as a tool for treatment selection. Among 47 (48%) EGFR-negative primary tumours, 35 cases (74%) were positive for phosphorylated Akt and MAPK. Among 51 (52%) EGFR-positive primary colorectal cancers, 13 (25%) cases were negative for phosphorylated Akt and 15 (29%) were negative for phosphorylated MAPK. In EGFR-negative metastases (56 cases, 55%), phosphorylated Akt was expressed in 41 (73%) and phosphorylated MAPK was expressed in 36 (64%) samples, whereas in EGFR-positive metastases, phosphorylated Akt and MAPK were negative in 14 (31%) and in 10 (22%) cases, respectively. Phosphorylated Akt expression in primary colorectal tumours changed from positive to negative in 16 (16%) paired metastases and from negative to positive in 13 (13%) related metastatic sites. Phosphorylated MAPK expression in primary tumours changed from positive to negative in 13 (13%) paired metastases and from negative to positive in 12 (12%) related metastatic sites. Our findings suggest that phosphorylated Akt and MAPK status in primary tumours does not correlate with Akt and MAPK status in corresponding metastases. EGFR downstream signalling pathway can be overactivated even in the absence of EGFR expression in a considerable proportion of patients.

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“…Since PKB/Akt is involved in such a multitude of apoptosis regulatory pathways, it is not surprising that Akt is overexpressed in a variety of human tumour cell lines and cancers (Bellacosa et al, 1995;Ringel et al, 2001;Roy et al, 2002) and a mediator of oestrogen resistance in breast cancer cells (Campbell et al, 2001). Akt activity in cancers can either be deregulated by constitutive activation or by mutation of PTEN/MMAC1, a phosphatase that directly counteracts Akt through the dephosphorylation of PI-3-, 4-, and 5-P 3 (Stambolic et al, 1998).…”

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confidence: 99%

Molecular alterations in apoptotic pathways after PKB/Akt-mediated chemoresistance in NCI H460 cells

Hövelmann¹,

Beckers

Schmidt³

2004

Br J Cancer

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Protein kinase B/Akt has been described as a central mediator of antiapoptotic signals in cancer cells. Furthermore, Akt has been shown to affect cell cycle progression and proliferative pathways and to possess a potential function in tumorigenesis and chemoresistance. In this study, we show that the ectopic expression of a constitutively active form of Akt1 (CA-Akt1) results in enhanced chemoresistance of NCI H460 human NSCLC cells towards a panel of chemotherapeutic agents. To understand the molecular alterations leading to impaired chemosensitivity mediated by activated Akt, we analysed various apoptotic pathways, including the activation of p53, caspases 3, 7, 8, and 9, release of cytochrome c from mitochondria, and the expression levels of proand antiapoptotic proteins such as Bcl-2, Bcl-x L , Bcl-x s , Bax, or Bfl-1. We observed that expression of CA-Akt did not interfere with single defined apoptotic switches, but modulated the apoptotic threshold of several apoptotic pathways towards increasing the threshold of onset. In particular, we found that CA-Akt-expressing cells displayed increased expression of the antiapoptotic Bcl-2 family member protein Bcl-x l , and a delayed onset of the p53 pathway after treatment with cisplatin or Mitoxantrone. Thus, our data suggest that Akt mediates chemoresistance in NHI H460 cells by interfering with and delaying the onset of various apoptotic pathways. A complete inactivation of apoptotic pathways was observed in none of the molecular alterations investigated. Our data strengthen the role of Akt as a central mediator of cell survival signals and/or chemoresistance and as an attractive target for cancer cell chemosensitisation.

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AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis

Cited by 313 publications

References 27 publications

Increased cell survival, migration, invasion, and Akt expression in PTHrP-overexpressing LoVo colon cancer cell lines

Increased cell survival, migration, invasion, and Akt expression in PTHrP-overexpressing LoVo colon cancer cell lines

Epidermal growth factor receptor (EGFR) downstream signalling pathway in primary colorectal tumours and related metastatic sites: optimising EGFR-targeted treatment options

Molecular alterations in apoptotic pathways after PKB/Akt-mediated chemoresistance in NCI H460 cells

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