A role for PI3K-Akt signaling in pulmonary metastatic nodule formation of the osteosarcoma cell line, LM8

Fukaya, Yasushi; Ishiguro, Naoki; Senga, Takeshi; Ichigotani, Yasukatsu; Sohara, Yasuyoshi; Tsutsui, Motomu; Shioura, Tomone; Iwamoto, Takashi; Hamaguchi, Michinari

doi:10.3892/or.14.4.847

Cited by 27 publications

(36 citation statements)

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“…Increased cellular invasion is often accompanied by increased activity of proteins that degrade the extracellular matrix such as members of the MMP family. In addition, the MAPK and PI3K pathways have been shown to regulate expression of MMP family members (31,37,38). Therefore, we assessed the activity and expression of several members of the MMP family in MCF7/PODXL and PC3/PODXL cells.…”

Section: Resultsmentioning

confidence: 99%

“…Ezrin has been shown to bind directly to phosphatidylinositol 3-kinase (PI3K) and influence a number of signaling pathways that affect cellular functions related to tumorigenesis and metastasis, including the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK-ERK1/2), PI3K-AKT, and Rho pathways (21,23,30). Ezrin-mediated effects on AKT and ERK1/2 activity have been linked to the ability of ezrin to promote tumor progression and metastasis (23,25,31). NHERF gene mutations have also been implicated in breast cancer (32).…”

Section: Introductionmentioning

confidence: 99%

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Podocalyxin Increases the Aggressive Phenotype of Breast and Prostate Cancer Cells In vitro through Its Interaction with Ezrin

et al. 2007

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Podocalyxin is an anti-adhesive transmembrane sialomucin that has been implicated in the development of more aggressive forms of breast and prostate cancer. The mechanism through which podocalyxin increases cancer aggressiveness remains poorly understood but may involve the interaction of podocalyxin with ezrin, an established mediator of metastasis. Here, we show that overexpression of podocalyxin in MCF7 breast cancer and PC3 prostate cancer cell lines increased their in vitro invasive and migratory potential and led to increased expression of matrix metalloproteases 1 and 9 (MMP1 and MMP9). Podocalyxin expression also led to an increase in mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) activity. To determine the role of ezrin in these podocalyxin-dependent phenotypic events, we first confirmed that podocalyxin formed a complex with ezrin in MCF7 and PC3 cells. Furthermore, expression of podocalyxin was associated with a changed ezrin subcellular localization and increased ezrin phosphorylation. Transient knockdown of ezrin protein abrogated MAPK and PI3K signaling as well as MMP expression and invasiveness in cancer cells overexpressing podocalyxin. These findings suggest that podocalyxin leads to increased in vitro migration and invasion, increased MMP expression, and increased activation of MAPK and PI3K activity in MCF7 and PC3 cells through its ability to form a complex with ezrin. [Cancer Res 2007;67(13):6183-91]

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Podocalyxin Increases the Aggressive Phenotype of Breast and Prostate Cancer Cells In vitro through Its Interaction with Ezrin

et al. 2007

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“…Our finding is supported by the recent report that inactivation of Akt by a dominant negative form of Akt could result in suppression of MMP secretion thus suppression of in vivo pulmonary cancer metastasis. 28 Recently, Harada et al 29 also reported that decreased expression of Akt phosphorylation and FGF-2 was correlated with decreased tumorigenicity and angiogenesis in vivo and such reduced angiogenesis was partly due to the blockade of Akt1 activity. Our results also demonstrated that suppression of Akt1 activity by lentivirus-mediated CTMP overexpression might be responsible for inhibition of tumor progression.…”

Section: Lentivirus-mediated Ctmp Gene Transfection S-k Hwang Et Almentioning

confidence: 99%

Lentivirus-mediated carboxyl-terminal modulator protein gene transfection via aerosol in lungs of K-ras null mice

et al. 2007

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The low efficiency of conventional therapies in achieving long-term survival of lung cancer patients calls for development of novel options. Aerosol gene delivery may provide the alternative for safe and effective treatment for lung cancer. Therefore, current study was performed to elucidate the potential effects of C-terminal modulator protein (CTMP) via aerosol on lung tumorigenesis. Lentiviral vector-CTMP was delivered into K-ras null lung cancer mice through the noseonly inhalation system for 30 min. After 48 h, the potential effects of CTMP on Akt1-related signals and cell cycle regulation in the lungs were evaluated by western blot, immunohistochemistry and zymography. Lentivirus-based CTMP delivery inhibited the Akt1 activity through selective suppression of Akt1 phosphorylation at Ser473. Aerosol delivery of CTMP inhibited proteins important for Akt1 signals, cell cycle and tumor metastasis in lungs of K-ras null mice. Together, our results suggest that lentivirusmediated aerosol delivery of CTMP may be compatible with noninvasive in vivo gene therapy. Our results emphasize the importance of noninvasive-targeted delivery of CTMP for lung cancer therapy in the future. While the studies are conducted in mice, it is envisioned that noninvasive targeting the specific genes responsible for cancer progression is an attractive strategy for effective anticancer therapeutics.

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“…[7][8][9][10] For example, studies have shown that over-activation of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is an important contributor of progression and chemo-resistance of malignant osteosarcoma. [7][8][9][10][11] PI3K, a heterodimer consisting of the p85 regulatory and p110 catalytic subunits, is a major signaling component downstream of receptor tyrosine kinases (RTKs). 12 PI3K activates its downstream Akt, which phosphorylates several substrates involved in various key cellular processes including cell growth, proliferation, survival, apoptosis-resistance and metabolism.…”

Section: Introductionmentioning

confidence: 99%

Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against osteosarcoma

Zhu¹,

Min

Fang³

et al. 2015

Cancer Biology & Therapy

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Keywords: MEK/Erk and chemo-resistance, NVP-BEZ235, osteosarcoma, PI3K-Akt-mTOR signaling Abbreviations: mammalian target of rapamycin (mTOR); mTOR complex 1 (mTORC1); mTOR complex 2 (mTORC2); phosphoinositide-dependent protein kinase-1 (PDK1); phosphatidylinositol 3-kinase (PI3K); receptor tyrosine kinases (RTKs).Recent studies have identified that constitutively active phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is an important feature of osteosarcoma, where it promotes cell proliferation, survival, and chemo-resistance. Here, we studied the therapeutic potential of NVP-BEZ235, a novel dual PI3K/mTOR dual inhibitor, on osteosarcoma cells in vivo and in vitro. NVP-BEZ235 was cytotoxic and cytostatic to a panel of osteosarcoma lines (MG-63, U2OS and SaOs-2), where it induce apoptosis and cell-cycle arrest. At the molecular level, NVP-BEZ235 inhibited PI3K-AKT-mTORC1 activation and downregulated cyclin D1/cyclin B1 expressions, while increasing MEK/Erk phosphorylation in osteosarcoma cells. MEK/Erk inhibitors PD98059 and MEK-162 increased NVP-BEZ235 activity on osteosarcoma cells. In vivo, oral NVP-BEZ235 inhibited U2OS xenograft in SCID mice, and its antitumor efficiency was further enhanced by MEK-162 co-administration. Taken together, our findings indicate that dual inhibition of PI3K and mTOR with NVP-BEZ235, either alone or in combination with MEK/Erk inhibitors, may be an efficient treatment for osteosarcoma.

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A role for PI3K-Akt signaling in pulmonary metastatic nodule formation of the osteosarcoma cell line, LM8

Cited by 27 publications

References 0 publications

Podocalyxin Increases the Aggressive Phenotype of Breast and Prostate Cancer Cells In vitro through Its Interaction with Ezrin

Podocalyxin Increases the Aggressive Phenotype of Breast and Prostate Cancer Cells In vitro through Its Interaction with Ezrin

Lentivirus-mediated carboxyl-terminal modulator protein gene transfection via aerosol in lungs of K-ras null mice

Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against osteosarcoma

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