{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:03:08Z","timestamp":1781103788804,"version":"3.54.1"},"reference-count":49,"publisher":"National Academy of Sciences","issue":"7","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"HHS | NIH | National Institute on Aging","doi-asserted-by":"publisher","award":["AG077574"],"award-info":[{"award-number":["AG077574"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010537","name":"Nebraska Department of Health and Human Services","doi-asserted-by":"publisher","award":["LB595"],"award-info":[{"award-number":["LB595"]}],"id":[{"id":"10.13039\/100010537","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"MOST | National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC3402100"],"award-info":[{"award-number":["2023YFC3402100"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"MOST | National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFA1105300"],"award-info":[{"award-number":["2022YFA1105300"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Science and Technology Innovation Key R&D Program of Chongqing","award":["CSTB2023TIAD-STX0002"],"award-info":[{"award-number":["CSTB2023TIAD-STX0002"]}]},{"name":"Science and Technology Innovation Key R&D Program of Chongqing","award":["CSTB2024TIAD-KPX0028"],"award-info":[{"award-number":["CSTB2024TIAD-KPX0028"]}]},{"DOI":"10.13039\/501100005230","name":"CSTC | Natural Science Foundation of Chongqing Municipality","doi-asserted-by":"publisher","award":["CSTB2023NSCQ-LZX0156"],"award-info":[{"award-number":["CSTB2023NSCQ-LZX0156"]}],"id":[{"id":"10.13039\/501100005230","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,2,17]]},"abstract":"<jats:p>The kinase MAPKAPK2 regulates cell survival, proliferation, and death, and is upregulated in colorectal carcinoma (CRC) where it is associated with tumor growth and progression. However, how it regulates tumor progression in conjunction with other signaling pathways, such as MEK\/ERK, remains elusive. Solid tumors are often subjected to metabolic stress, notably glucose deprivation. Here, we demonstrate that MAPKAPK2 protein levels in CRC regulate cell fate decision during stress conditions, such as glucose deprivation and therapeutic treatment. While MAPKAPK2 expression is a limiting factor for CRC growth in vitro, depleting MAPKAPK2 or inhibiting its activity pharmacologically provides a survival advantage to CRC cells under glucose limiting conditions. Subjecting CRC cells to low glucose resulted in an ERK1\/2-mediated decline in MAPKAPK2 to promote survival. Additionally, cells with reduced MAPKAPK2 activity were less sensitive to trametinib under glucose limiting conditions. Utilizing transcriptomic profiling, we found that glucose deprivation and MAPKAPK2 depletion activate pathways associated with survival during metabolic stress. This relationship was also observed in CRC patients (TCGA), where tumors with low MAPKAPK2 expression had higher ERK1\/2 activation and upregulated stress-induced pathways, leading to poor survival. Finally, MAPKAPK2 modulated growth of CRC organoids, subcutaneous tumors, and patient-derived xenografts (PDX), and reduced MAPKAPK2 levels decreased efficacy of trametinib, in vitro and in vivo. Overall, this study identifies an interrelationship between MEK\/ERK and p38\/MAPKAPK2 signaling pathways during glucose deprivation to support cell survival and features MAPKAPK2 loss as a possible mechanism leading to reduced efficacy of trametinib-based anticancer therapy and poor patient outcomes in CRC.<\/jats:p>","DOI":"10.1073\/pnas.2505331123","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T20:01:13Z","timestamp":1770667273000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic stress conditions dictate MAPKAPK2-dependent efficiency of MEK1\/2 inhibition in colorectal carcinoma"],"prefix":"10.1073","volume":"123","author":[{"given":"Niti","family":"Kumari","sequence":"first","affiliation":[{"name":"Biomedical Sciences Department, Creighton University School of Medicine","place":["Omaha"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0170-1005","authenticated-orcid":false,"given":"Xu","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University","place":["Chongqing, People\u2019s Republic of China"]},{"name":"Jinfeng Laboratory","place":["Chongqing, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber M.","family":"Baldwin","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Department, Creighton University School of Medicine","place":["Omaha"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin I.","family":"Clemons","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Department, Creighton University School of Medicine","place":["Omaha"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3014-3937","authenticated-orcid":false,"given":"Mohammad","family":"El-Harakeh","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Department, Creighton University School of Medicine","place":["Omaha"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilian E.","family":"Calisto","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Department, Creighton University School of Medicine","place":["Omaha"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balawant","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Hepatology and Motility, The University of Kansas","place":["Kansas City, KS"]},{"name":"Medical Center","place":["Kansas City, KS"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaoqiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jinfeng Laboratory","place":["Chongqing, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Min","sequence":"additional","affiliation":[{"name":"Gastrointestinal Surgery Department, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Xiao","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chongqing Medical University","place":["Chongqing, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amar B.","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology, Hepatology and Motility, The University of Kansas","place":["Kansas City, KS"]},{"name":"Medical Center","place":["Kansas City, KS"]},{"name":"The Kansas City VA Medical Center","place":["Kansas City, MO"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5574-1760","authenticated-orcid":false,"given":"Bin","family":"Wang","sequence":"additional","affiliation":[{"name":"Jinfeng Laboratory","place":["Chongqing, People\u2019s Republic of China"]},{"name":"Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University)","place":["Chongqing, People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0463-7028","authenticated-orcid":false,"given":"Brian J.","family":"North","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Department, Creighton University School of Medicine","place":["Omaha"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,2,9]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21708"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11888-018-0420-y"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-022-01358-5"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22126262"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2014.2367"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2017.345"},{"key":"e_1_3_4_7_2","first-page":"1997","article-title":"ERK\/MAPK signalling pathway and tumorigenesis","volume":"19","author":"Guo Y. J.","year":"2020","unstructured":"Y. J. Guo , ERK\/MAPK signalling pathway and tumorigenesis. Exp. Ther. Med. 19, 1997\u20132007 (2020).","journal-title":"Exp. Ther. Med."},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0582-8"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cr.7290105"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2012.05.006"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(02)02562-7"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C000917200"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-7859rev"},{"key":"e_1_3_4_14_2","unstructured":"https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-grants-accelerated-approval-dabrafenib-combination-trametinib-unresectable-or-metastatic-solid."},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02181-8"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.00762"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-1226"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-005332"},{"key":"e_1_3_4_19_2","first-page":"334","article-title":"Phase II trial of trametinib and panitumumab in RAS\/RAF wild type metastatic colorectal cancer","volume":"20","author":"Alshammari K.","year":"2021","unstructured":"K. Alshammari , Phase II trial of trametinib and panitumumab in RAS\/RAF wild type metastatic colorectal cancer. Clin. Colorectal Cancer 20, 334\u2013341 (2021).","journal-title":"Clin. Colorectal Cancer"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2020.102137"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-11309-7"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2015.07.052"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1805683115"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.29716"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-19-0553"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.21484"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1412152111"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2024562118"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00220-9"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.0022-3042.2001.00756.x"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.566430"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(05)70168-6"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v20.i29.9744"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-23-1148"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP280572"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines8090316"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2019.00004"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40164-018-0116-7"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm4007"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-12-86"},{"key":"e_1_3_4_41_2","doi-asserted-by":"crossref","unstructured":"L. Zhang . Predictive value of intratumoral-metabolic heterogeneity derived from (18)F-FDG PET\/CT in distinguishing microsatellite instability status of colorectal carcinoma. Front Oncol 13 1065744 (2023).","DOI":"10.3389\/fonc.2023.1065744"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13195009"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.18970"},{"key":"e_1_3_4_44_2","doi-asserted-by":"crossref","unstructured":"L. Yan Targeting Glucose Metabolism Sensitizes Pancreatic Cancer to MEK Inhibition. Cancer Res 81 4054-4065 (2021).","DOI":"10.1158\/0008-5472.CAN-20-3792"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1244917"},{"key":"e_1_3_4_46_2","article-title":"Detection of ubiquitylated proteins in mammalian cells","volume":"2006","author":"Tansey W. P.","year":"2006","unstructured":"W. P. Tansey, Detection of ubiquitylated proteins in mammalian cells. CSH Protoc. 2006, pdb.prot4616 (2006).","journal-title":"CSH Protoc."},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-023-00715-8"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-25-0252"},{"key":"e_1_3_4_49_2","unstructured":"N. Kumari B. J. North Data from \u201cTranscriptome analysis of HCT116 cells subjected to low glucose or depleted of MAPKAPK2 expression.\u201d Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE291324. Deposited 6 March 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2505331123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T20:08:27Z","timestamp":1770667707000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2505331123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,9]]},"references-count":49,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,2,17]]}},"alternative-id":["10.1073\/pnas.2505331123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2505331123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,9]]},"assertion":[{"value":"2025-03-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2505331123"}}