mTOR Signaling in Endometrial Cancer: From a Molecular and Therapeutic Point of View

Oda, Katsutoshi; Ikeda, Yuji; Kawana, Kei; Osuga, Yutaka; Fujii, Tomoyuki

doi:10.1007/s13669-014-0103-x

Cited by 11 publications

(9 citation statements)

References 86 publications

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“…Further investigations were warranted to elucidate the mechanism underlying autophagy induced by corilagin. Previous research has been shown that AMPK activation inhibits the rapamycin (mTOR) signalling pathway . Depending on the binding partners and sensitivities to rapamycin, mTOR resides in at least two distinct complexes, termed mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) .…”

Section: Discussionmentioning

confidence: 99%

Corilagin inhibits breast cancer growth via reactive oxygen species‐dependent apoptosis and autophagy

Tong

Zhang

Yang

et al. 2018

J Cellular Molecular Medi

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Corilagin is a component of Phyllanthus urinaria extract and has been found of possessing anti‐inflammatory, anti‐oxidative, and anti‐tumour properties in clinic treatments. However, the underlying mechanisms in anti‐cancer particularly of its induction of cell death in human breast cancer remain undefined. Our research found that corilagin‐induced apoptotic and autophagic cell death depending on reactive oxygen species (ROS) in human breast cancer cell, and it occurred in human breast cancer cell (MCF‐7) only comparing with normal cells. The expression of procaspase‐8, procaspase‐3, PARP, Bcl‐2 and procaspase‐9 was down‐regulated while caspase‐8, cleaved PARP, caspase‐9 and Bax were up‐regulated after corilagin treatment, indicating apoptosis mediated by extrinsic and mitochondrial pathways occurred in MCF‐7 cell. Meanwhile, autophagy mediated by suppressing Akt/mTOR/p70S6K pathway was detected with an increase in autophagic vacuoles and LC3‐II conversion. More significantly, inhibition of autophagy by chloroquine diphosphate salt (CQ) remarkably enhanced apoptosis, while the caspase inhibitor z‐VAD‐fmk failed in affecting autophagy, suggesting that corilagin‐induced autophagy functioned as a survival mechanism in MCF‐7 cells. In addition, corilagin induced intracellular reactive oxygen species (ROS) generation, when reduced by ROS scavenger NAC, apoptosis and autophagy were both down‐regulated. Nevertheless, in SK‐BR3 cell which expressed RIP3, necroptosis inhibitor Nec‐1 could not alleviate cell death induced by corilagin, indicating necroptosis was not triggered. Subcutaneous tumour growth in nude mice was attenuated by corilagin, consisting with the results in vitro. These results imply that corilagin inhibits cancer cell proliferation through inducing apoptosis and autophagy which regulated by ROS release.

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Section: Discussionmentioning

confidence: 99%

Corilagin inhibits breast cancer growth via reactive oxygen species‐dependent apoptosis and autophagy

Tong

Zhang

Yang

et al. 2018

J Cellular Molecular Medi

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“…Mutations in PTEN and KRAS have been identified frequently in endometrial cancer . A gain of function mutation in KRAS activates both the mitogen‐activated protein kinase (MAPK) pathway and the PI3K pathway, whereas a loss of function mutation in PTEN activates the PI3K pathway . In addition to these alterations, we found various types of mutations in the RAS/PI3K pathway, including PIK3CA , AKT1 , and reduction in the chromosomal copy number of NF1 (a negative regulator of RAS) .…”

Section: Coexistent Activating Mutations In the Ras/pi3k Pathway Potementioning

confidence: 90%

“…Therefore, multiple inputs may have additive effects to enhance the activity of the PI3K pathway. There are various types of AKT effectors in the PI3K/mTOR pathway, and the activity of each AKT effector may vary according to the level of PI3K activity and/or the type of alterations in this pathway . One of the important roles of PIK3CA is to promote malignant transformation in pre‐malignant tumor cells.…”

Section: Coexistent Activating Mutations In the Ras/pi3k Pathway Potementioning

confidence: 99%

Characterization of TP53 and PI3K signaling pathways as molecular targets in gynecologic malignancies

Oda

Ikeda

Kashiyama

et al. 2016

J of Obstet and Gynaecol

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Recent developments in genomic analysis have unveiled the key signaling pathways in human cancer. However, only a limited number of molecular-targeted drugs are applicable for clinical use in gynecologic malignancies. TP53 signaling and phosphatidylinositol 3 kinase pathways are frequently mutated in cancer, and have received much attention as molecular targets in human cancers. In this review, we mainly focus on the functions of these pathways, and discuss the molecular-targeted drugs under clinical trials. The molecular-targeted drugs described in this review include dual phosphatidylinositol 3 kinase/mTOR inhibitors (NVP-BEZ235, DS-7423, SAR245409), an mTOR inhibitor (everolimus), an MEK inhibitor (pimasertib), an autophagy inhibitor (chloroquine), a cyclin-dependent kinases 4/6 inhibitor (PD0332991), and a poly (ADP-ribose) polymerase inhibitor (olaparib).

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“…Third, we confirmed that the combination of an mTOR inhibitor and pimasertib did not show a synergistic effect in the endometrial cancer cells, regardless of their sensitivity to pimasertib. In the past, we have shown that the dual PI3K/mTOR inhibitor NVP-BEZ235 provides more robust growth suppression than the mTOR inhibitor everolimus in endometrial cancer cell lines [12,18]. Moreover, low-dose rapamycin has been found to be sufficient to suppress phosphorylation of S6 [43].…”

Section: Discussionmentioning

confidence: 99%

“…In preclinical studies, the antitumor effect of PI3K pathway inhibitors has been demonstrated in a panel of endometrial cancer cell lines [12,13]. mTOR inhibitors including everolimus, temsirolimus, and a combination of bevacizumab and temsirolimus have been evaluated in endometrial cancer patients [14][15][16][17][18]. However, the response rate of mTOR inhibition alone was b10%, and no mTOR inhibitor has been approved for the treatment of endometrial cancer.…”

mentioning

confidence: 99%

Antitumor activity of a combination of dual PI3K/mTOR inhibitor SAR245409 and selective MEK1/2 inhibitor pimasertib in endometrial carcinomas

Inaba

Oda

Ikeda

et al. 2015

Gynecologic Oncology

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mTOR Signaling in Endometrial Cancer: From a Molecular and Therapeutic Point of View

Cited by 11 publications

References 86 publications

Corilagin inhibits breast cancer growth via reactive oxygen species‐dependent apoptosis and autophagy

Corilagin inhibits breast cancer growth via reactive oxygen species‐dependent apoptosis and autophagy

Characterization of TP53 and PI3K signaling pathways as molecular targets in gynecologic malignancies

Antitumor activity of a combination of dual PI3K/mTOR inhibitor SAR245409 and selective MEK1/2 inhibitor pimasertib in endometrial carcinomas

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