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PEM suppresses the activities of several enzymes involved in purine and pyrimidine synthesis, and elevated activity of these enzymes in tumors is often linked with resistance to PEM. The agent also stimulates AMP\u2010activated protein kinase (AMPK) and consequently influences the mammalian target of rapamycin complex 1 (mTORC1) pathways. Nevertheless, it remains unclear whether PEM resistance is linked to the AMPK or mTORC1 pathways. Here, we established two independent PEM\u2010resistant mesothelioma cell lines in which expression of the PEM\u2010target enzymes was not elevated, and found that levels of phosphorylated AMPK and p70S6K and, to a lesser extent, levels of phosphorylated AKT and p53, were increased in these cells as compared with the respective parent cells. PEM stimulation also augmented phosphorylation of AMPK, p70S6K, AKT and p53 in most cases. An AMPK activator increased phosphorylation and PEM resistance in parental cells, and the inhibitor decreased the resistance of PEM\u2010resistant cells. In contrast, inhibitors for p70S6K and AKT did not influence PEM resistance; furthermore, increased levels of endogenous p53 did not affect PEM sensitivity. These data collectively indicate that constitutive activation of AMPK is associated with PEM resistance, and that this is unconnected with elevated DNA and RNA synthesis.<\/jats:p>","DOI":"10.1002\/1878-0261.12496","type":"journal-article","created":{"date-parts":[[2019,4,29]],"date-time":"2019-04-29T10:49:26Z","timestamp":1556534966000},"page":"1419-1432","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["AMPK activation induced in pemetrexed\u2010treated cells is associated with development of drug resistance independently of target enzyme expression"],"prefix":"10.1002","volume":"13","author":[{"given":"Yiyang","family":"Qin","sequence":"first","affiliation":[{"name":"Division of Pathology and Cell Therapy Chiba Cancer Center Research Institute Japan"},{"name":"Laboratory of Molecular Cell Biology Graduate School of Pharmaceutical Sciences Chiba University 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