Molecular analysis ofPTEN andMXI1 in primary bladder carcinoma

Wang, David S.; Rieger-Christ, Kimberly; Latini, Jerilyn M.; Moinzadeh, Ali; Stoffel, John T.; Pezza, John A.; Saini, Kulvinder Singh; Libertino, John A.; Summerhayes, Ian C.

doi:10.1002/1097-0215(20001115)88:4<620::aid-ijc16>3.0.co;2-z

Cited by 64 publications

(53 citation statements)

References 18 publications

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“…These cell lines, J82 and UM-UC-3, express N-cadherin in the absence of Ecadherin and lack PTEN protein due to homozygous deletion of the gene (Wang et al, 2000). The PI3 kinase inhibitor (LY294002) and the Akt inhibitor both reduced invasion, further implicating the Akt signaling pathway as a primary event in invasive bladder cell behavior.…”

Section: Discussionmentioning

confidence: 98%

“…Both cells lines lack PTEN expression owing to homozygous deletion of the gene (Wang et al, 2000) and consequently display constitutively activated Akt signaling. To examine whether Akt signaling plays an important role in the invasion of these cell lines, invasion assays were performed in the presence of LY294002, Akt inhibitor and also in the presence of PP2.…”

Section: Inhibition Of Constitutively Activated Akt In Highly Invasivmentioning

confidence: 99%

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Novel expression of N-cadherin elicits in vitro bladder cell invasion via the Akt signaling pathway

et al. 2004

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Novel N-cadherin expression has been linked to the invasive phenotype in bladder tumors yet a primary role for N-cadherin in invasion has not been defined in this model. To address this, N-cadherin was stably transfected into E-cadherin expressing bladder carcinoma cells. This resulted in an enhanced invasive capacity in in vitro assays that was blocked by incubation with an N-cadherin function-blocking antibody in a dose-dependent manner. Analysis of the signaling pathway(s) implicated in N-cadherin-mediated invasion in bladder carcinoma cell lines revealed no correlation between MAPK signaling and invasion, in the presence or absence of fibroblast growth factor 2. Also, while MAPK and p38 kinase inhibitors did not alter the invasive behavior of these cells, an increase in the phosphorylation of Akt at serine-473 was detected in N-cadherin transfectants, suggestive of N-cadherin-mediated Akt activation in bladder cell invasion. Incubation of N-cadherin transfectants with either PI3 kinase or Akt inhibitors resulted in a significant decrease in the invasive capacity of these cells. Exposure of cells to PP2, a src family kinase inhibitor, also decreased the invasive potential of N-cadherin transfectants and resulted in reduced phosphorylation of Akt. The involvement of Akt signaling in bladder cell invasion was also supported by the inhibition of bladder cell invasion by cells constitutively expressing an activated Akt kinase, using the PI3 kinase and Akt inhibitors and PP2. These results suggest that activation of PI3/AKT kinase following N-cadherin expression contributes to the increased invasive potential of bladder carcinoma cells.

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Section: Discussionmentioning

confidence: 98%

Section: Inhibition Of Constitutively Activated Akt In Highly Invasivmentioning

confidence: 99%

Novel expression of N-cadherin elicits in vitro bladder cell invasion via the Akt signaling pathway

et al. 2004

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“…The T24T cell line was recently characterized in our laboratory (Gildea et al, 2000a) as a highly invasive and metastatic variant (Gildea et al, 2002b) of T24. T24, which expresses a functionally deficient PTEN (Liu et al, 2000;Tanaka et al, 2000;Wang et al, 2000), HT1197 (Liu et al, 2000;Tanaka et al, 2000), which has a wild-type PTEN, and UM-UC-3 (Liu et al, 2000;Tanaka et al, 2000), which is null for PTEN, were obtained from the American Tissue Culture Collection (ATCC, Rockville, MD, USA). J82 bladder cancer cells, LNCaP, DU145 and PC-3 human prostate cancer cells were obtained from the American Tissue Culture Collection (ATCC, Rockville, MD, USA).…”

Section: Cell Linesmentioning

confidence: 99%

“…PTEN was also identified as the gene predisposing to Cowden disease, an autosomal dominant cancer predisposition syndrome associated with an increased risk of breast, skin and thyroid tumors and occasional cases of bladder and renal cell carcinoma (Li et al, 1997;Steck et al, 1997). Several investigators have specifically looked at loss of 10q23 and/or PTEN mutation in bladder cancers (Cappellen et al, 1997;Cairns et al, 1998;Aveyard et al, 1999;Wang et al, 2000). While these studies indicate that the PTEN gene is altered only in a minority of bladder cancers, its loss appears associated with a more invasive and malignant phenotype.…”

Section: Introductionmentioning

confidence: 99%

PTEN can inhibit in vitro organotypic and in vivo orthotopic invasion of human bladder cancer cells even in the absence of its lipid phosphatase activity

et al. 2004

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Recent studies have found a higher frequency of the PTEN tumor-suppressor gene alterations in invasive bladder carcinoma than in superficial disease, suggesting that PTEN is important in this process. A role of PTEN in bladder cancer invasion is further suggested by the fact that PTEN is a regulator of cell motility, a necessary component of tumor invasion. However, it is unknown whether PTEN is mechanistically involved in 'in vivo' tumor invasion or merely an epiphenomenon and, if the former is true, whether this process is dependent on its protein or lipid phosphatase activities. To address these issues, we stably transfected several commonly used human bladder cancer cell lines with known invasive phenotypes with either wild-type PTEN constructs or those deficient in the lipid phosphatase (G129E) or both protein and lipid phosphatase (G129R) activities. Here we show that chemotaxis was inhibited by both the wild-type and G129E mutant of PTEN but not by G129R-transfected cells. Using a novel organotypic in vitro invasion assay, we evaluated the impact of wild-type and mutant PTEN transgene expression on the invasive ability of T24T, a human bladder cancer cell line with a functionally impaired PTEN. Results indicate that the G129E mutant blocks invasion as efficiently as wild-type PTEN transfection. In contrast to the wild-type gene, this mutant has no effect on cell clonogenicity in agar. To further establish the role of PTEN in tumor invasion, we evaluated vector-and PTEN-transfected T24T cells in an orthotopic in vivo assay that faithfully reproduces human disease. Microscopic examination of murine bladders at the completion of this experiment parallels the results obtained with the organotypic assay. Our results are the first demonstration: (1) that the inhibitory effects of PTEN on cell motility translate into suppression of in vivo invasion; (2) that PTEN can inhibit tumor invasion even in the absence of its lipid phosphatase activity; (3) how organotypic in vitro approaches can be used as surrogates of in vivo invasion allowing rapid dissection of molecular processes leading to this phenotype while reducing the number of animals used in research.

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“…In bladder cancer, mutations have been identified in PIK3CA (Lopez- Knowles et al, 2006) and TSC1 (which lies downstream of AKT in the PI3 kinase-AKT-mTOR branch of the PI3 kinase pathway) (Knowles et al, 2003;Pymar et al, 2008), and loss of heterozygosity, homozygous deletion and inactivating mutations of PTEN have been found (Cappellen et al, 1997;Cairns et al, 1998;Aveyard et al, 1999;Wang et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

AKT1 mutations in bladder cancer: identification of a novel oncogenic mutation that can co-operate with E17K

et al. 2009

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The phosphatidylinositol-3-kinase (PI3 kinase)-AKT pathway is frequently activated in cancer. Recent reports have identified a transforming mutation of AKT1 in breast, colorectal, ovarian and lung cancers. We report here the occurrence of this mutation in bladder tumours. The AKT1 G49A (E17K) mutation was found in 2/44 (4.8%) bladder cancer cell lines and 5/184 (2.7%) bladder tumours. Cell lines expressing mutant AKT1 show constitutive AKT1 activation under conditions of growth factor withdrawal. We also detected a novel AKT1 mutation G145A (E49K). This mutation also enhances AKT activation and shows transforming activity in NIH3T3 cells, though activity is weaker than that of E17K. Enhanced activation of AKT1 when E17K and E49K mutations are in tandem suggests that they can co-operate.

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Molecular analysis ofPTEN andMXI1 in primary bladder carcinoma

Cited by 64 publications

References 18 publications

Novel expression of N-cadherin elicits in vitro bladder cell invasion via the Akt signaling pathway

Novel expression of N-cadherin elicits in vitro bladder cell invasion via the Akt signaling pathway

PTEN can inhibit in vitro organotypic and in vivo orthotopic invasion of human bladder cancer cells even in the absence of its lipid phosphatase activity

AKT1 mutations in bladder cancer: identification of a novel oncogenic mutation that can co-operate with E17K

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