EC:2.7.11.31 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.31 (AMP-activated protein kinase)
13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ovarian cancer is one of the major cancer types. NK-92 cell line, which has consistently and reproducibly high anti-tumor cytotoxicity, may be used for immunotherapy against ovarian cancer. Understanding the mechanisms that regulate the anti-tumor activity of NK-92 cells is important for developing novel therapeutic strategies. In the current study, using an ovarian cancer xenograft mouse model, we identified the up-regulation of sestrin2 (SESN2) and sestrin3 (SESN3) in intratumoral NK-92 cells. Lentivirus-transduced NK-92 cells, which overexpressed SESN2 or SESN3 after doxycycline treatment, exhibited less expression of activating receptors, perforin and granzyme B. Overexpression of SESN2 and SESN3 impaired tumoricidal effect of NK-92 cells both in vitro and in vivo. Furthermore, overexpression of SESN2 and SESN3 inhibited mTORC1 signaling while promoting AMPK signaling in NK-92 cells. Taken together, our data highlights the crucial effects of SESN2 and SESN3 on NK-92 cell-mediated anti-ovarian cancer activity. This study might be valuable for designing a novel therapeutic strategy for ovarian cancer.
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PMID:Sestrin2 and sestrin3 suppress NK-92 cell-mediated cytotoxic activity on ovarian cancer cells through AMPK and mTORC1 signaling. 2916 16

Cytotoxic T lymphocytes (CTL) and natural killer cells (NK)-mediated elimination of tumor cells is mostly dependent on Granzyme B apoptotic pathway, which is regulated by the wild type (wt) p53 protein. Because TP53 inactivating mutations, frequently found in human tumors, could interfere with Granzyme B-mediated cell death, the use of small molecules developed to reactivate wtp53 function in p53-mutated tumor cells could optimize their lysis by CTL or NK cells. Here, we show that the pharmalogical reactivation of a wt-like p53 function in p53-mutated breast cancer cells using the small molecule CP-31398 increases their sensitivity to NK-mediated lysis. This potentiation is dependent on p53-mediated induction of autophagy via the sestrin-AMPK-mTOR pathway and the ULK axis. This CP31398-induced autophagy sequestrates in autophagosomes several anti-apoptotic proteins, including Bcl-X_L and XIAP, facilitating Granzyme B-mediated mitochondrial outer membrane permeabilization, caspase-3 activation and Granzyme B- or NK cell-induced apoptosis. Together, our results define a new way to increase cytotoxic lymphocyte-mediated lysis of p53-mutated breast cancer cell, through a p53-dependent autophagy induction, with potential applications in combined immunotherapeutic approaches.
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PMID:The pharmalogical reactivation of p53 function improves breast tumor cell lysis by granzyme B and NK cells through induction of autophagy. 3154 Oct 80

Metabolism is reprogrammed in cancer to fulfill the demands of malignant cells for cancer initiation and progression. Apart from its effects within cancer cells, little is known about whether and how reprogramed metabolism regulates the surrounding tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSC) are key regulators of the TME and greatly affect tumor progression and therapeutic responses. In this study, our results revealed that retinol metabolism-related genes and enzymes were significantly downregulated in human colorectal cancer compared with adjacent colonic tissues, and tumors exhibited a defect in retinoic acid (RA) synthesis. Reduced ADH1-mediated retinol metabolism was associated with attenuated RA signaling and accumulated MDSCs in colorectal cancer tumors. Using an in vitro model, generating MDSCs from CD34⁺ myeloid precursors, we found that exogenous RA could abrogate the generation of polymorphonuclear MDSCs (PMN-MDSC) with negligible impact on myeloid differentiation. Mechanistically, RA could restrain the glycolytic capacity of myeloid cells, which in turn activated the AMP-activated protein kinase (AMPK) pathway, further impairing the suppressive capacity of myeloid cells. Supplementation with RA could significantly delay tumor growth, with reduced arginase-1-expressing myeloid cells and increased CD8⁺ and granzyme B⁺ T cells in both colitis-associated and implanted MC38 mouse colorectal cancer models. Our results indicated that the defect in ADH1-mediated RA synthesis could provide a possible mechanism that fosters the generation of PMN-MDSCs in colorectal cancer and that restoring RA signaling in the TME could serve as a promising therapeutic strategy to abrogate the generation of PMN-MDSCs.
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PMID:Retinoic Acid Synthesis Deficiency Fosters the Generation of Polymorphonuclear Myeloid-Derived Suppressor Cells in Colorectal Cancer. 3317 8