PubMed:28696138 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/28696138","sourcedb":"PubMed","sourceid":"28696138","text":"ADIPOQ/adiponectin induces cytotoxic autophagy in breast cancer cells through STK11/LKB1-mediated activation of the AMPK-ULK1 axis.\nADIPOQ/adiponectin, an adipocytokine secreted by adipocytes in the breast tumor microenvironment, negatively regulates cancer cell growth hence increased levels of ADIPOQ/adiponectin are associated with decreased breast cancer growth. However, its mechanisms of action remain largely elusive. We report that ADIPOQ/adiponectin induces a robust accumulation of autophagosomes, increases MAP1LC3B-II/LC3B-II and decreases SQSTM1/p62 in breast cancer cells. ADIPOQ/adiponectin-treated cells and xenografts exhibit increased expression of autophagy-related proteins. LysoTracker Red-staining and tandem-mCherry-GFP-LC3B assay show that fusion of autophagosomes and lysosomes is augmented upon ADIPOQ/adiponectin treatment. ADIPOQ/adiponectin significantly inhibits breast cancer growth and induces apoptosis both in vitro and in vivo, and these events are preceded by macroautophagy/autophagy, which is integral for ADIPOQ/adiponectin-mediated cell death. Accordingly, blunting autophagosome formation, blocking autophagosome-lysosome fusion or genetic-knockout of BECN1/Beclin1 and ATG7 effectively impedes ADIPOQ/adiponectin induced growth-inhibition and apoptosis-induction. Mechanistic studies show that ADIPOQ/adiponectin reduces intracellular ATP levels and increases PRKAA1 phosphorylation leading to ULK1 activation. AMPK-inhibition abrogates ADIPOQ/adiponectin-induced ULK1-activation, LC3B-turnover and SQSTM1/p62-degradation while AMPK-activation potentiates ADIPOQ/adiponectin's effects. Further, ADIPOQ/adiponectin-mediated AMPK-activation and autophagy-induction are regulated by upstream master-kinase STK11/LKB1, which is a key node in antitumor function of ADIPOQ/adiponectin as STK11/LKB1-knockout abrogates ADIPOQ/adiponectin-mediated inhibition of breast tumorigenesis and molecular analyses of tumors corroborate in vitro mechanistic findings. ADIPOQ/adiponectin increases the efficacy of chemotherapeutic agents. Notably, high expression of ADIPOQ receptor ADIPOR2, ADIPOQ/adiponectin and BECN1 significantly correlates with increased overall survival in chemotherapy-treated breast cancer patients. Collectively, these data uncover that ADIPOQ/adiponectin induces autophagic cell death in breast cancer and provide in vitro and in vivo evidence for the integral role of STK11/LKB1-AMPK-ULK1 axis in ADIPOQ/adiponectin-mediated cytotoxic autophagy.","tracks":[{"project":"Tester","denotations":[{"id":"T1","span":{"begin":50,"end":63},"obj":"breast cancer"},{"id":"T2","span":{"begin":345,"end":358},"obj":"breast cancer"},{"id":"T3","span":{"begin":566,"end":579},"obj":"breast cancer"},{"id":"T4","span":{"begin":893,"end":906},"obj":"breast cancer"},{"id":"T5","span":{"begin":2226,"end":2239},"obj":"breast cancer"},{"id":"T6","span":{"begin":2340,"end":2353},"obj":"breast cancer"},{"id":"T7","span":{"begin":50,"end":63},"obj":"Breast Cancer"},{"id":"T8","span":{"begin":345,"end":358},"obj":"Breast Cancer"},{"id":"T9","span":{"begin":566,"end":579},"obj":"Breast Cancer"},{"id":"T10","span":{"begin":893,"end":906},"obj":"Breast Cancer"},{"id":"T11","span":{"begin":2226,"end":2239},"obj":"Breast Cancer"},{"id":"T12","span":{"begin":2340,"end":2353},"obj":"Breast Cancer"},{"id":"T13","span":{"begin":57,"end":63},"obj":"Cancer"},{"id":"T14","span":{"begin":251,"end":257},"obj":"Cancer"},{"id":"T15","span":{"begin":352,"end":358},"obj":"Cancer"},{"id":"T16","span":{"begin":573,"end":579},"obj":"Cancer"},{"id":"T17","span":{"begin":900,"end":906},"obj":"Cancer"},{"id":"T18","span":{"begin":2233,"end":2239},"obj":"Cancer"},{"id":"T19","span":{"begin":2347,"end":2353},"obj":"Cancer"},{"id":"T20","span":{"begin":57,"end":63},"obj":"Cancers"},{"id":"T21","span":{"begin":251,"end":257},"obj":"Cancers"},{"id":"T22","span":{"begin":352,"end":358},"obj":"Cancers"},{"id":"T23","span":{"begin":573,"end":579},"obj":"Cancers"},{"id":"T24","span":{"begin":900,"end":906},"obj":"Cancers"},{"id":"T25","span":{"begin":2233,"end":2239},"obj":"Cancers"},{"id":"T26","span":{"begin":2347,"end":2353},"obj":"Cancers"},{"id":"T27","span":{"begin":199,"end":211},"obj":"Breast Tumor"},{"id":"T28","span":{"begin":199,"end":211},"obj":"Breast Tumors"},{"id":"T29","span":{"begin":206,"end":211},"obj":"Tumor"},{"id":"T30","span":{"begin":1943,"end":1949},"obj":"Tumor"},{"id":"T31","span":{"begin":206,"end":211},"obj":"Tumors"},{"id":"T32","span":{"begin":1943,"end":1949},"obj":"Tumors"},{"id":"T33","span":{"begin":1077,"end":1082},"obj":"Death"},{"id":"T34","span":{"begin":2331,"end":2336},"obj":"Death"},{"id":"T35","span":{"begin":1903,"end":1916},"obj":"Tumorigenesis"},{"id":"T36","span":{"begin":1903,"end":1916},"obj":"Tumorigeneses"}],"attributes":[{"subj":"T1","pred":"source","obj":"Tester"},{"subj":"T2","pred":"source","obj":"Tester"},{"subj":"T3","pred":"source","obj":"Tester"},{"subj":"T4","pred":"source","obj":"Tester"},{"subj":"T5","pred":"source","obj":"Tester"},{"subj":"T6","pred":"source","obj":"Tester"},{"subj":"T7","pred":"source","obj":"Tester"},{"subj":"T8","pred":"source","obj":"Tester"},{"subj":"T9","pred":"source","obj":"Tester"},{"subj":"T10","pred":"source","obj":"Tester"},{"subj":"T11","pred":"source","obj":"Tester"},{"subj":"T12","pred":"source","obj":"Tester"},{"subj":"T13","pred":"source","obj":"Tester"},{"subj":"T14","pred":"source","obj":"Tester"},{"subj":"T15","pred":"source","obj":"Tester"},{"subj":"T16","pred":"source","obj":"Tester"},{"subj":"T17","pred":"source","obj":"Tester"},{"subj":"T18","pred":"source","obj":"Tester"},{"subj":"T19","pred":"source","obj":"Tester"},{"subj":"T20","pred":"source","obj":"Tester"},{"subj":"T21","pred":"source","obj":"Tester"},{"subj":"T22","pred":"source","obj":"Tester"},{"subj":"T23","pred":"source","obj":"Tester"},{"subj":"T24","pred":"source","obj":"Tester"},{"subj":"T25","pred":"source","obj":"Tester"},{"subj":"T26","pred":"source","obj":"Tester"},{"subj":"T27","pred":"source","obj":"Tester"},{"subj":"T28","pred":"source","obj":"Tester"},{"subj":"T29","pred":"source","obj":"Tester"},{"subj":"T30","pred":"source","obj":"Tester"},{"subj":"T31","pred":"source","obj":"Tester"},{"subj":"T32","pred":"source","obj":"Tester"},{"subj":"T33","pred":"source","obj":"Tester"},{"subj":"T34","pred":"source","obj":"Tester"},{"subj":"T35","pred":"source","obj":"Tester"},{"subj":"T36","pred":"source","obj":"Tester"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"Tester","color":"#d493ec","default":true}]}]}}