title: Sensitization of cancer cells through reduction of total Akt and downregulation of salinomycin-induced pAkt, pGSk3β, pTSC2, and p4EBP1 by cotreatment with MK-2206.
abstract: MK-2206 is an inhibitor of Akt activation. It has been investigated as an anticancer drug in clinical trials assessing the potential of pAkt targeting therapy. The purpose of this study was to identify conditions that increase the sensitivity of cancer cells to MK-2206. We found that the treatment of cancer cells with a high concentration of salinomycin (Sal) reduced total Akt protein levels but increased activated Akt levels. When cancer cells were cotreated with MK-2206 and Sal, both pAkt and total Akt levels were reduced. Using microscopic observation, an assessment of cleaved PARP, FACS analysis of pre-G1 region, and Hoechst staining, we found that Sal increased apoptosis of MK-2206-treated cancer cells. These results suggest that cotreatment with MK-2206 and Sal sensitizes cancer cells via reduction of both pAkt and total Akt. Furthermore, cotreatment of cancer cells with Sal and MK-2206 reduced pp70S6K, pmTOR, and pPDK1 levels. In addition, Sal-induced activation of GSK3β, TSC2, and 4EBP1 was abolished by MK-2206 cotreatment. These results suggest that cotreatment using MK-2206 and Sal could be used as a therapeutic method to sensitize cancer cells through targeting of the PI3K/Akt/mTOR pathway. Our findings may contribute to the development of MK-2206-based sensitization therapies for cancer patients.
authors.affiliation: Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do 411-764, Republic of Korea.
authors.forename: Ae-Ran
authors.initials: AR
authors.lastname: Choi
authors.affiliation: Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do 411-764, Republic of Korea.
authors.forename: Ju-Hwa
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do 411-764, Republic of Korea.
authors.forename: Sungpil
authors.initials: S
authors.lastname: Yoon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000032:analysis / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D010750:Phosphoproteins / Q000032:analysis / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis / Q000378:metabolism*; D011714:Pyrans / Q000494:pharmacology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000378:metabolism; D000095662:Polyether Polyketides
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006575:Heterocyclic Compounds, 3-Ring; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D011714:Pyrans; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C087000:EIF4EBP1 protein, human; C548887:MK 2206; C000624653:TSC2 protein, human; C010327:salinomycin; D000095662:Polyether Polyketides; C000605506:GSK3B protein, human