PRAS40 signaling in tumor

Lv, Dan; Guo, Long; Zhang, Ting; Huang, Lin

doi:10.18632/oncotarget.17299

Cited by 51 publications

(47 citation statements)

References 71 publications

(145 reference statements)

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“…PRAS40 is a downstream target of AKT, a component of the mTOR complex 1 (mTORC1) that regulates mTOR activity, and when phosphorylated dissociates from mTORC1 so that it can function . PRAS40 is increasingly used as a biomarker of AKT activation in tumors . The mTOR inhibitor sirolimus (rapamycin) has been used to treat KLA patients with a partial response in KLA patients .…”

Section: Discussionmentioning

confidence: 99%

“…[15][16][17][18][19] In the Glaser study, 6 PRAS40 is increasingly used as a biomarker of AKT activation in tumors. 21 The mTOR inhibitor sirolimus (rapamycin) has been used to treat KLA patients with a partial response in KLA patients. 2 24 and has now been granted "Fast Track" designation by the Food and Drug Administration for the treatment of PROS as well as Rare Pediatric Disease designation for the treatment of Proteus syndrome.…”

Section: Discussionmentioning

confidence: 99%

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Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis

Boscolo

Pastura

Glaser

et al. 2019

Pediatric Blood & Cancer

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Background Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly with significant morbidity and mortality. KLA is characterized by diffuse multifocal lesions comprised of focal areas of “kaposiform” spindled cells accompanying malformed lymphatic channels. The goal of this study was to identify activated signaling pathways in cells isolated from three KLA patients for the purpose of testing new therapies. Procedure Cells were obtained from the lungs of one patient isolated at autopsy and the spleen of two patients removed in surgery due to disease complications. A protein kinase array was performed on the KLA cell lysates and normal lymphatic endothelial cells. Results Higher activation of key signaling pathways in the KLA cells, including PRAS40, AKT1/2/3, and ERK‐1/2, was identified by protein kinase array and confirmed by Western blot analysis. This indicated a role for highly activated PI3K–AKT and MAPK–ERK‐1/2 signaling pathways in KLA cells. Cell proliferation studies assessed PI3K inhibitors (LY294002; BYL719), AKT inhibitor ARQ092, mTOR inhibitor rapamycin, and MAPK inhibitor U0126. These studies demonstrated that PI3K–AKT–mTOR and MAPK signaling are important mediators of KLA cell proliferation. BYL719 and rapamycin were more effective at inhibiting KLA cell proliferation than U0126. Conclusions Our studies using cells from KLA patient lesions demonstrate that these cells are highly proliferative and the PI3K–AKT–mTOR and MAPK pathways are promising therapeutic targets. Development and clinical trials of PI3K, AKT, and MAPK inhibitors for cancer treatment and the data in this study lend support for early clinical trials assessing the efficacy of these inhibitors in KLA patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis

Boscolo

Pastura

Glaser

et al. 2019

Pediatric Blood & Cancer

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“…This observation suggests that the PI3K/Akt and mTOR pathways might be involved in the anticancer activity of 3. The cytoplasmic form of PRAS40 is indeed known to play a role in the regulation of these two signaling pathways by directly regulating the mTORC1 kinase activity [33,34]. To determine whether p53 phosphorylation on serine 15 was a result of DNA damage induced by 3, MCF7-Sh-WISP2 cells were immuno-labelled with the γ-H2AX antibody following exposure to 3 ( Figure S4).…”

Section: Cytotoxic Activity Of 1-4 Toward Mcf7 Mcf7-sh-wisp2 and 3t3mentioning

confidence: 99%

Secondary Metabolites from the Culture of the Marine-derived Fungus Paradendryphiella salina PC 362H and Evaluation of the Anticancer Activity of Its Metabolite Hyalodendrin

et al. 2020

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High-throughput screening assays have been designed to identify compounds capable of inhibiting phenotypes involved in cancer aggressiveness. However, most studies used commercially available chemical libraries. This prompted us to explore natural products isolated from marine-derived fungi as a new source of molecules. In this study, we established a chemical library from 99 strains corresponding to 45 molecular operational taxonomic units and evaluated their anticancer activity against the MCF7 epithelial cancer cell line and its invasive stem cell-like MCF7-Sh-WISP2 counterpart. We identified the marine fungal Paradendryphiella salina PC 362H strain, isolated from the brown alga Pelvetia caniculata (PC), as one of the most promising fungi which produce active compounds. Further chemical and biological characterizations of the culture of the Paradendryphiella salina PC 362H strain identified (-)-hyalodendrin as the active secondary metabolite responsible for the cytotoxic activity of the crude extract. The antitumor activity of (-)-hyalodendrin was not only limited to the MCF7 cell lines, but also prominent on cancer cells with invasive phenotypes including colorectal cancer cells resistant to chemotherapy. Further investigations showed that treatment of MCF7-Sh-WISP2 cells with (-)-hyalodendrin induced changes in the phosphorylation status of p53 and altered expression of HSP60, HSP70 and PRAS40 proteins. Altogether, our study reveals that this uninvestigated marine fungal crude extract possesses a strong therapeutic potential against tumor cells with aggressive phenotypes and confirms that members of the epidithiodioxopiperazines are interesting fungal toxins with anticancer activities.

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“…6e, f). We then detected the level of p-p70S6K, a major downstream target of mTOC1, because the dephosphorylation of PRAS40 and AMPK activation could both indirectly inhibit mTOC1 activity to negatively regulate protein synthesis [17][18][19] . The results revealed that the phosphorylation of p70S6K was strongly repressed in response to the increased p-AMPK and decreased p-PRAS40 caused by PTP1B inhibition (Fig.…”

Section: Ptp1b Regulates Pancreatic Cancer Cell Growth Via the Pkm2/amentioning

confidence: 99%

Inhibition of PTP1B blocks pancreatic cancer progression by targeting the PKM2/AMPK/mTOC1 pathway

et al. 2019

Cell Death Dis

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Pancreatic cancer is a highly malignant cancer and lacks effective therapeutic targets. Protein-tyrosine phosphatase 1B (PTP1B), a validated therapeutic target for diabetes and obesity, also plays a critical positive or negative role in tumorigenesis. However, the role of PTP1B in pancreatic cancer remains elusive. Here, we initially demonstrated that PTP1B was highly expressed in pancreatic tumors, and was positively correlated with distant metastasis and tumor staging, and indicated poor survival. Then, inhibition of PTP1B either by shRNA or by a specific small-molecule inhibitor significantly suppressed pancreatic cancer cell growth, migration and colony formation with cell cycle arrest in vitro and inhibited pancreatic cancer progression in vivo. Mechanism studies revealed that PTP1B targeted the PKM2/ AMPK/mTOC1 signaling pathway to regulate cell growth. PTP1B inhibition directly increased PKM2 Tyr-105 phosphorylation to further result in significant activation of AMPK, which decreased mTOC1 activity and led to inhibition of p70S6K. Meanwhile, the decreased phosphorylation of PRAS40 caused by decreased PKM2 activity also helped to inhibit mTOC1. Collectively, these findings support the notion of PTP1B as an oncogene and a promising therapeutic target for PDAC.

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PRAS40 signaling in tumor

Cited by 51 publications

References 71 publications

Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis

Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis

Secondary Metabolites from the Culture of the Marine-derived Fungus Paradendryphiella salina PC 362H and Evaluation of the Anticancer Activity of Its Metabolite Hyalodendrin

Inhibition of PTP1B blocks pancreatic cancer progression by targeting the PKM2/AMPK/mTOC1 pathway

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