MMAC1/PTEN inhibits cell growth and induces chemosensitivity to doxorubicin in human bladder cancer cells

Tanaka, Motoyoshi; Koul, Dimpy; Davies, Michael A.; Liebert, Monica; Steck, Peter A.; Grossman, H. Barton

doi:10.1038/sj.onc.1203918

Cited by 93 publications

(74 citation statements)

References 33 publications

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“…Our data confirm previous reports that adenovirusmediated transfer of wild-type PTEN inhibits tumor growth by UM-UC-3 and T24 cells (Tanaka et al, 2000). The T24 cells used in this study were probably most similar to our T24T cells, since they were tumorigenic (Liu et al, 2000).…”

Section: Discussionsupporting

confidence: 81%

“…The T24 lineage cells used in these experiments are a faithful model of invasive human bladder cancer by virtue of their EGFR overexpression (Lipponen and Eskelinen, 1994), H-Ras mutation (Fontana et al, 1996), functional inactivation of PTEN (Liu et al, 2000;Tanaka et al, 2000), as well as by the invasive ability of T24T in orthotopic assays (Gildea et al, 2000a). These cell lines are an excellent model in which to compare and contrast genetic and phenotypic differences associated with the acquisition of tumorigenicity and aggressiveness.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Cell Linesmentioning

confidence: 99%

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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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“…18,19 Our present results suggest that PTEN-positive tumors might be more sensitive to chemotherapy than negative or mixed tumors. The relationship between PTEN and chemosensitivity should be studied in endometrial carcinoma.…”

Section: Resultsmentioning

confidence: 54%

PTEN expression is associated with prognosis for patients with advanced endometrial carcinoma undergoing postoperative chemotherapy

Kanamori

Kigawa

Itamochi

et al. 2002

Intl Journal of Cancer

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The prognostic significance of PTEN expression in endometrial carcinoma has not been clear. We conducted the present study to clarify the relationship between PTEN expression and prognosis in advanced endometrial carcinoma. 4 showed that PTEN ϩ/-mice over 6 months old frequently developed endometrial carcinoma. These findings suggest that PTEN is strongly involved in the development and/or progression of endometrial carcinoma.Studies have also shown the relationship between PTEN and prognosis in several cancers, including endometrial carcinoma. However, these results are controversial. In 2 studies, loss of PTEN expression was related to poor prognosis in glioblastoma and prostate cancer. 5,6 In contrast, PTEN mutation was associated with favorable survival in endometrial carcinoma. 7 Two issues make it difficult to evaluate PTEN as a prognostic factor in endometrial carcinoma. First, because about 75% of patients with endometrial carcinoma present with stage I disease, which has a good prognosis, 8 a large number of advanced cases are needed to analyze survival rates meaningfully. Second, PTEN mutations are observed predominantly in endometrioid carcinomas and not in nonendometrioid subtypes, such as serous or clear cell, which are aggressive and have poor prognosis. [1][2][3]8 To examine the influence of PTEN, it is necessary to select endometrioid carcinoma.To clarify the prognostic significance of PTEN, we investigated the relationship between its expression and prognosis in a large number of patients with advanced endometrioid endometrial carcinoma. MATERIAL AND METHODS PatientsA total of 784 patients with endometrial carcinoma underwent primary treatment between 1985 and 2000 at Tottori University Hospital, Kurume University Hospital, National Defense Medical School Hospital, Jichi Medical School Hospital or Kawasaki Medical School Hospital (Japan). Of the 784 patients, 98 who met the following criteria were entered in the study: pure endometrioid carcinoma, undergoing surgical staging and positive retroperitoneal lymph nodes. All subjects underwent hysterectomy, bilateral salpingo-oophorectomy and pelvic and/or para-aortic lymphadenectomy. Postoperative treatment was performed according to each institutional protocol. As a result, 25 patients received wholepelvis and/or para-aortic irradiation and 62 patients received platinum-based chemotherapy. The remaining 11 patients did not have any treatment because of their poor physical condition. Eightyseven (88.8%) patients were in FIGO stage IIIc and 11 (11.2%) in stage IV. Mean age was 58.6 (range 30 -78) years. All patients provided informed consent for research use of their samples. Immunohistochemic stainingA 4 m section was cut from the paraffin block of a primary uterine tumor. Each section was mounted on a silane-coated glass slide, deparaffinized and soaked for 15 min at room temperature in 0.3% H 2 O 2 /methanol to block endogenous peroxidase. A mouse anti-PTEN monoclonal antibody, PTEN A2B1 (Santa Cruz Biotechnology, Santa Cruz, CA) was applied for ...

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“…1A). Because the lack of functional PTEN in T24 cells (12) could contribute to this phenotype, we examined the occurrence of this phenomenon in MCF7 breast cancer cells, which express functional PTEN (13). As was the case in T24 cells, brief exposure of MCF7 cells to GA led to increased phosphorylation of Akt on Ser-473 (Fig.…”

Section: Ga Transiently Activates Akt and Erk Via Phosphatidylinositomentioning

confidence: 99%

Hsp90 inhibition transiently activates Src kinase and promotes Src-dependent Akt and Erk activation

Koga

Karpova

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

109

112

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Hsp90 plays an essential role in maintaining stability and activity of its clients, including oncogenic signaling proteins that regulate key signal transduction nodes. Hsp90 inhibitors interfere with diverse signaling pathways by destabilizing and attenuating activity of such proteins, and thus they exhibit antitumor activity. However, Hsp90 inhibition has recently been reported to activate Akt and Erk and potentiate Akt activation induced by insulin-like growth factor 1 and insulin, raising the concern that clinical use of Hsp90 inhibitors might promote tumor progression under certain circumstances. Here, we show that the prototypical Hsp90 inhibitor geldanamycin induces Akt and Erk activation that is independent of PTEN status and is mediated by transient activation of Src kinase. Activated Src phosphorylates Cbl, which recruits the p85 subunit of phosphatidylinositol 3-kinase, resulting in phosphatidylinositol 3-kinase activation and eventually the activation of Akt and Erk. We show that geldanamycin rapidly disrupts Src association with Hsp90, suggesting that Src activation results directly from dissociation of the chaperone. These data suggest that, under certain circumstances, dual inhibition of Hsp90 and Src may be warranted.cancer ͉ chaperone ͉ geldanamycin

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MMAC1/PTEN inhibits cell growth and induces chemosensitivity to doxorubicin in human bladder cancer cells

Cited by 93 publications

References 33 publications

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

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

PTEN expression is associated with prognosis for patients with advanced endometrial carcinoma undergoing postoperative chemotherapy

Hsp90 inhibition transiently activates Src kinase and promotes Src-dependent Akt and Erk activation

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