Akt activation in renal cell carcinoma: contribution of a decreased PTEN expression and the induction of apoptosis by an Akt inhibitor

Hará, Saburo; Oya, Mototsugu; Mizuno, Ryuichi; Horiguchi, Akio; Marumo, Ken; Murai, Masaru

doi:10.1093/annonc/mdi182

Cited by 86 publications

(53 citation statements)

References 13 publications

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“…6C). Consistently, 1L-6-hydroxymethyl-chiroinositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate (a specific AKT inhibitor) at 10 Amol/L treatment (38,39) increased the baicalein-induced cell death (Fig. 6D).…”

Section: Existence Of Survivin Increases the Cell Proliferation And Rsupporting

confidence: 62%

Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT

Liu

2007

Molecular Cancer Therapeutics

127

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The bioactive flavonoid baicalein has been shown to have in vitro growth-inhibitory activity in human cancer cells, although the mechanism of action is poorly understood. Baicalein (40 -80 Mmol/L for 24 h) more effectively induced cytotoxicity compared with other flavonoids (baicalin, catechin, genistein, quercetin, and rutin) in bladder cancer cells. Baicalein induced cell proliferation inhibition and apoptosis. The levels of cyclin B1 and phospho-CDC2 (Thr 161 ) were reduced, whereas the G 2 -M phases were elevated by baicalein. Treatment of CDC2 kinase or CDC25 phosphatase inhibitors augments the baicalein-induced cytotoxicity. A variety of human bladder cancer cell lines expressed survivin proteins, which were located on the mitotic phases and regulated mitotic progression. Baicalein markedly reduced survivin protein expression. Transfection of a survivin small interfering RNA diminished the level of survivin proteins and increased the baicalein-mediated cell death. Overexpression of survivin enhanced cell proliferation and resisted the baicalein-induced cytotoxicity. Interestingly, baicalein induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and AKT. SB203580, a specific p38 MAPK inhibitor, attenuated proliferation inhibition and restored the protein levels of phospho-CDC2 (Thr 161 ) and survivin in the baicalein-exposed cells; conversely, blockade of AKT activation enhanced cytotoxicity and the reduction of phospho-CDC2 (Thr 161 ) and survivin proteins.As a whole, these findings provide that the opposite role of p38 MAPK and AKT regulates CDC2 kinase and survivin and the inhibition of CDC2-survivin pathway by baicalein contributes to apoptosis and proliferation retardation in cancer cells.

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Section: Existence Of Survivin Increases the Cell Proliferation And Rsupporting

confidence: 62%

Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT

Liu

2007

Molecular Cancer Therapeutics

127

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“…37,38 Reduced PTEN protein expression has been found in a high frequency in RCC and is associated with PKB/Akt activation in ccRCC, but interestingly not in pRCC. 2,39 The collected data suggests that in ccRCC the PTEN directed regulation of the PI-3 kinase pathway is affected by both genetic aberrations in the PTEN gene and by DJ-1 gene expression levels.…”

Section: Discussionmentioning

confidence: 99%

“…In RCC, an association between decreased PTEN expression and high PKB/Akt activation has been described. 2 A novel protein, DJ-1 (also called Cap1/RS/PARK7), has been proposed to be involved in tumorigenesis by negatively regulating PTEN. 3 DJ-1 was first described as a protein showing a cooperative transforming activity with H-Ras in mouse NIH3T3 cells.…”

mentioning

confidence: 99%

The PTEN regulator DJ‐1 is associated with hTERT expression in clear cell renal cell carcinoma

Sitaram

Cairney

Grabowski

et al. 2009

Intl Journal of Cancer

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DJ-1 is as a novel regulator of the tumor suppressor PTEN with stimulatory effects on PI3K-AKT/PKB signaling, one possible target of which is cMyc. The catalytic unit of the telomerase complex, hTERT, can be activated at different levels, including transcriptionally by cMyc and through phosphorylation by AKT/PKB. The aim of the study was to analyze the putative signaling pathway encompassing DJ-1, cMyc and hTERT in a series of 176 renal cell carcinomas (RCC) and experimentally in cell lines. DJ-1 mRNA expression was significantly elevated in clear cell RCC (ccRCC) compared with in papillary RCC (pRCC; p 5 0.005) and kidney cortex tissue (p < 0.001). ccRCC and pRCC demonstrated higher cMyc RNA levels than in kidney cortex (p < 0.001 for both) as well as increased levels of hTERT RNA (p < 0.001 and p 5 0.011, respectively). DJ-1 was positively correlated to cMyc and hTERT in ccRCC (p < 0.001 and p 5 0.019, respectively), but not in pRCC, indicating that this pathway could have a functional significance in ccRCC. siRNA knock down of DJ-1 induced downregulation of cMyc and hTERT mRNA associated with decreased expression of pAKT and cMyc protein levels. hTERT promoter activity was upregulated after DJ-1 transfection and this upregulation was inhibited after mutation of the cMyc binding sites. These experimental data support the functional link among DJ-1, cMyc and hTERT expression as indicated in the tumor material. Neither DJ-1, cMyc nor hTERT mRNA levels were associated with proliferation (S-phase fraction), telomere length or prognosis in ccRCC. ' UICCKey words: renal cell carcinoma; DJ-1; cMyc; hTERT; telomere length; proliferation; prognosis Renal cell carcinoma (RCC) constitutes a heterogeneous group of tumors regarding cytogenetic aberrations, morphologic appearance and clinical outcome. The WHO classification identifies different morphologic subtypes of sporadic RCC including the three most common types, clear cell (ccRCC), papillary (pRCC) and chromophobe RCC. 1 Each entity shows characteristic cytogenetic abnormalities indicating essential differences between the RCC subtypes regarding the mechanisms leading to tumor development.The phosphatase tensin homologue deleted on chromosome 10 (PTEN) protein is a well known tumor suppressor acting as a negative regulator of the phosphoinositide-3 (PI-3)-kinase pathway including the downstream Protein Kinase B (PKB)/Akt protein. In RCC, an association between decreased PTEN expression and high PKB/Akt activation has been described. 2 A novel protein, DJ-1 (also called Cap1/RS/PARK7), has been proposed to be involved in tumorigenesis by negatively regulating PTEN. 3 DJ-1 was first described as a protein showing a cooperative transforming activity with H-Ras in mouse NIH3T3 cells. 4 Overexpression of DJ-1 has been reported in several malignancies, including breast and lung. 5,6 Further, DJ-1 mRNA expression levels seemed to be associated with survival in lung cancer 3 and elevated levels of circulating DJ-1 and anti-DJ-1 auto-antibodies were detected in breast cance...

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“…Whether these mechanisms have a function in the clinical activity of rapalogues in renal cell carcinomas remain unknown. Several clear cell carcinoma cell lines express high AKT levels and reduced PTEN expressions that render them potentially sensitive to mTOR inhibition (Hara et al, 2005). Activity of mTORC1 inhibitors, particularly temsirolimus, in renal cell cancer has raised the possibility that responders share a common molecular phenotype that renders these tumours dependent on mTOR for growth and/or survival.…”

Section: Differential Review Of Biological Effects Of Mtor Inhibitionmentioning

confidence: 99%

mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work?

et al. 2008

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The proof of principle that a drug targeting mTOR can improve survival has been obtained recently from a large randomised trial using temsirolimus as a first-line therapy in patients with advanced poor prognostic renal cell carcinoma. Consistent data have recently shown the important role of the PI3K/AKT/mTOR signalling pathway in the regulation of crucial metabolic and mitotic functions of cancer cells and endothelial cells allowing a better understanding of the role of mTOR in controlling cancer cell proliferation and survival as well as tumour angiogenesis. As a result, rapamycin derivatives (rapalogues) that block mTOR/Raptor complex 1 were shown to exert direct antiproliferative effects against endometrial cancers, in which cancer cells frequently lose PTEN function as well as mantle cell lymphomas, in which cancer cell proliferation appears to be driven primarily by cyclin D1 overexpression. The overall antitumour effects of rapalogues in renal cell carcinoma appear to be more complex with tumour growth inhibition resulting from direct G1/S cell cycle blockage and/or apoptotic effects in carcinoma cells along with the inhibition of downstream signalling of the HIF1a-induced VEGF/VEGFR autocrine loop in endothelial cells shutting down the maintenance of tumour angiogenesis. Despite extensive cognitive researches, it is difficult to appraise which of those mechanisms is predominant in patients. This review focuses on mechanisms of action of rapalogues focusing on antitumour effects in patients with renal cell carcinoma.

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Akt activation in renal cell carcinoma: contribution of a decreased PTEN expression and the induction of apoptosis by an Akt inhibitor

Abstract: A decreased expression of PTEN may be an underlying mechanism for Akt activation. An Akt inhibitor may be a therapeutic option for a subset of RCC with an elevated Akt activity.

Cited by 86 publications

References 13 publications

Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT

Baicalein induces cancer cell death and proliferation retardation by the inhibition of CDC2 kinase and survivin associated with opposite role of p38 mitogen-activated protein kinase and AKT

The PTEN regulator DJ‐1 is associated with hTERT expression in clear cell renal cell carcinoma

mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work?

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