AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth

Altomare, Deborah A.; Wang, Hui Qin; Skele, Kristine L.; Rienzo, Assunta De; Klein‐Szanto, Andres J.; Godwin, Andrew K.; Testa, Joseph R.

doi:10.1038/sj.onc.1207721

Cited by 379 publications

(321 citation statements)

References 15 publications

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“…Importantly, compared to the effects of LY294002, a potent PI3-K/AKT signalling pathway inhibitor (Altomare et al, 2004), IC 50 of OSU-03012 is several folds lower in RMS cells. These results indicate that novel OSU-03012 compound may be a more potent inhibitor to PDK-1/AKT pathway than the currently potent inhibitor of PI3-K/AKT, LY294002 to treat childhood RMSs.…”

Section: Discussionmentioning

confidence: 92%

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

et al. 2007

Br J Cancer

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Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma including two major subtypes, alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS). Increasing evidence suggests that oncogenesis of RMS involves multistages of signalling protein dysregulation which may include prolonged activation of serine/threonine kinases such as phosphoinositide-dependant kinase-1 (PDK-1) and AKT. To date, whether PDK-1/AKT pathway is activated in RMS is unknown. This study was to examine phosphorylation status of AKT and to evaluate a novel small molecular inhibitor, OSU-03012 targeting PDK-1 in RMS. We examined phosphorylation levels of AKT using ARMS and ERMS tissue microarray and immunohistochemistry staining. Our results showed phospho-AKT Thr308 level is elevated 42 and 35% in ARMS and ERMS, respectively. Phospho-AKT Ser473 level is also increased 43% in ARMS and 55% in ERMS. Furthermore, we showed that OSU-03012 inhibits cell viability and induces apoptosis in ARMS and ERMS cell lines (RH30, SMS-CTR), which express elevated phospho-AKT levels. Normal cells are much less sensitive to OSU-03012 and in which no detectable apoptosis was observed. This study showed, for the first time, that PDK-1/AKT pathway is activated in RMS and may play an important role in survival of RMS. PDK-1/AKT pathway may be an attractive therapeutic target for cancer intervention in RMS using OSU-03012.

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Section: Discussionmentioning

confidence: 92%

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

et al. 2007

Br J Cancer

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“…It has been reported that phosphorylation of Akt and mTOR, an Akt substrate, was frequently detected in ovarian cancer (Altomare et al, 2004). In animal model of ovarian cancer, LY294002, a potent inhibitor of Akt activation, could inhibit cancer growth and ascites formation (Hu et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells

et al. 2006

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Y-box-binding protein 1 (YB-1), which is a member of the DNA-binding protein family containing a cold-shock domain, has pleiotropic functions in response to various environmental stimuli. As we previously showed that YB-1 is a global marker of multidrug resistance in ovarian cancer and other tumor types. To identify YB-1-regulated genes in ovarian cancers, we investigated the expression profile of YB-1 small-interfering RNA (siRNA)-transfected ovarian cancer cells using a high-density oligonucleotide array. YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. Exogenous serum addition stimulated YB-1 translocation from the cytoplasm to the nucleus, and treatment with Akt inhibitors as well as Akt siRNA and integrin-linked kinase (ILK) siRNA specifically blocked YB-1 nuclear localization. Inhibition of Akt activation downregulated CXCR4 and upregulated MDR1 (ABCB1) gene expression. Administration of Akt inhibitor resulted in decrease in nuclear YB-1-positive cancer cells in a xenograft animal model. Akt activation thus regulates the nuclear translocation of YB-1, affecting the expression of drug-resistance genes and other genes associated with the malignant characteristics in ovarian cancer cells. Therefore, the Akt pathway could be a novel target of disrupting the nuclear translocation of YB-1 that has important implications for further development of therapeutic strategy against ovarian cancers.

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“…Expression of PTEN in ovarian cancer cells suppresses tumor growth (25,26) and its deletion in the mouse ovarian surface epithelium leads to preneoplastic ovarian lesions (27), indicating a strong role for this protein in ovarian cancer etiology. There is ample evidence for the role of the overactivated prosurvival PI3K/Akt pathway in ovarian cancer carcinogenesis (14,15). There is only one study on the effect of sulforaphane on the Akt pathway, which suggests an induction of the pathway in CaCo-2 cells (28).…”

Section: Discussionmentioning

confidence: 99%

“…Deregulation of the Akt pathway has been observed in many cancer types, including breast, endometrial, thyroid cancers, and melanoma (12,13). Components of the PI3K/Akt pathway are frequently overexpressed in ovarian cancer (14,15) and are thought to play major roles in ovarian cancer carcinogenesis. The overexpression of the Akt pathway is frequently associated with poor prognosis and more aggressive phenotype (16).…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative activity of sulforaphane in Akt-overexpressing ovarian cancer cells

Chaudhuri

Oršulić

Ashok

2007

Molecular Cancer Therapeutics

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Epidemiologic studies show a correlation between increased consumption of fruits and vegetables with reduced risk of ovarian cancer. One major bioactive compound found in cruciferous vegetables, particularly broccoli, is sulforaphane, derived from the breakdown of glucoraphanin. We observed potent antiproliferative effects of sulforaphane on human ovarian cancer cell line SKOV3 (IC 50 40 Mmol/L) and mouse ovarian cancer cell lines C3 and T3 (IC 50 25 Mmol/L each) by cell viability assays. The loss of viability is reflected by a downregulation of cell cycle transition regulators cyclin D1, cyclin-dependent kinase 4 (cdk4), and cdk6. The upstream mediators of sulforaphane effects on the cell cycle in ovarian cancer are still unknown. However, because the Akt signal transduction pathway is overactivated in ovarian cancer, we investigated the effects of sulforaphane on this prosurvival pathway. Both total Akt protein and active phosphorylated levels of Akt (Ser 473 ) and phosphoinositide 3-kinase were significantly decreased in sulforaphane-treated SKOV3, C3, and T3 cells with a concomitant inhibition of Akt kinase activity by sulforaphane in SKOV3 and C3 cells. This inhibitory effect of sulforaphane leads to a potent induction of apoptosis in all three cell lines, along with the cleavage of poly(ADP)-ribose polymerase. Our study is the first to report the antiproliferative effects of sulforaphane in ovarian cancer and identifying the Akt pathway as a target of sulforaphane, with implications for the inhibition of carcinogenesis by diet-based chemoprevention. [Mol Cancer Ther 2007;6(1):334 -45]

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AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth

Cited by 379 publications

References 15 publications

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

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

Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells

Antiproliferative activity of sulforaphane in Akt-overexpressing ovarian cancer cells

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