{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:53:22Z","timestamp":1790949202543,"version":"4.1.0"},"reference-count":80,"publisher":"American Chemical Society (ACS)","issue":"10","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Gastric cancer is driven by aberrant kinase signaling that promotes uncontrolled proliferation and metabolic adaptations. Although calcium\/calmodulin-dependent protein kinase 2 (CAMKK2) is overexpressed in gastric cancer, its role in regulating tumor-associated metabolic programs remains unclear. Here, we employed an integrated multiomics approach, centered on untargeted metabolomics, to investigate the effects of CAMKK2 inhibition in gastric cancer cells. Pharmacological inhibition of CAMKK2 using STO-609 resulted in G1\/S phase cell cycle arrest, multinucleation, and coordinated metabolic, proteomic, and phosphoproteomic alterations. Metabolomic profiling revealed extensive metabolic reprogramming characterized by the depletion of purine and pyrimidine intermediates required for DNA synthesis. Pathway analysis demonstrated the suppression of nucleotide, lipid, and central carbon metabolism, indicating impaired biosynthetic capacity. Integration with proteomic and phosphoproteomic datasets revealed coordinated downregulation of DNA replication machinery and attenuation of signaling pathways involved in cell cycle progression. Collectively, these findings suggest that CAMKK2 contributes to the coordination of metabolic and signaling programs associated with DNA replication and proliferation in gastric cancer. CAMKK2 inhibition was associated with the coordinated depletion of nucleotide metabolites and disruption of replication-associated signaling, consistent with impaired DNA replication and a replication-stress-like phenotype. These findings highlight CAMKK2 as a potential therapeutic target for exploiting metabolic vulnerabilities in gastric cancer.<\/jats:p>","DOI":"10.1021\/acs.jproteome.6c00428","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:01:43Z","timestamp":1789444903000},"page":"5493-5511","source":"Crossref","is-referenced-by-count":0,"title":["Integrated\nMetabolomic, Proteomic, and Phosphoproteomic\nProfiling Reveals Metabolic and Signaling Alterations Associated with\nCAMKK2 Inhibition in Gastric Cancer"],"prefix":"10.1021","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3044-3772","authenticated-orcid":true,"given":"Mohd Altaf","family":"Najar","sequence":"first","affiliation":[{"name":"Yenepoya (Deemed to be University) , , ,","place":["Mangalore, India, 575018"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikita","family":"Choudhary","sequence":"additional","affiliation":[{"name":"Yenepoya (Deemed to be University) , , ,","place":["Mangalore, India, 575018"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nidhi","family":"Dwivedi","sequence":"additional","affiliation":[{"name":"Yenepoya (Deemed to be University) , , ,","place":["Mangalore, India, 575018"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4817-3379","authenticated-orcid":true,"given":"Prashant Kumar","family":"Modi","sequence":"additional","affiliation":[{"name":"Yenepoya (Deemed to be University) , , ,","place":["Mangalore, India, 575018"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"issue":"3","key":"2026100208420169000_cit1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and\nmortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"Ca-Cancer J. 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Gastroenterol."},{"issue":"1","key":"2026100208420169000_cit5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1349-7006.2005.00006.x","article-title":"Salt, salted\nfood intake, and risk of gastric cancer: epidemiologic evidence","volume":"96","author":"Tsugane","year":"2005","journal-title":"Cancer Sci."},{"issue":"40","key":"2026100208420169000_cit6","doi-asserted-by":"publisher","first-page":"14537","DOI":"10.3748\/wjg.v20.i40.14537","article-title":"Clinical management\nof advanced gastric cancer: the role of new molecular drugs","volume":"20","author":"De Vita","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"2026100208420169000_cit7","doi-asserted-by":"publisher","first-page":"103038","DOI":"10.1016\/j.ctrv.2025.103038","article-title":"Precision oncology in gastric cancer: Shaping\nthe future of personalized\ntreatment","volume":"141","author":"Migliore","year":"2025","journal-title":"Cancer Treat Rev."},{"key":"2026100208420169000_cit8","doi-asserted-by":"publisher","first-page":"118513","DOI":"10.1016\/j.lfs.2020.118513","article-title":"PI3K\/AKT\/mTOR signaling in gastric cancer: Epigenetics\nand beyond","volume":"262","author":"Fattahi","year":"2020","journal-title":"Life Sci."},{"issue":"1","key":"2026100208420169000_cit9","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1038\/s41392-022-01190-w","article-title":"Signaling pathways and therapeutic interventions in\ngastric cancer","volume":"7","author":"Lei","year":"2022","journal-title":"Signal Transduction Targeted\nTher."},{"issue":"1","key":"2026100208420169000_cit10","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1186\/s12967-024-05998-8","article-title":"The role of\nMAPK pathway in gastric cancer: unveiling molecular crosstalk and\ntherapeutic prospects","volume":"22","author":"Yuan","year":"2024","journal-title":"J. Transl. Med."},{"issue":"1","key":"2026100208420169000_cit11","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e41457","article-title":"The role of cell cycle-related\ngenes in the tumorigenesis of adrenal\nand thyroid neuroendocrine tumors","volume":"11","author":"Filipovich","year":"2025","journal-title":"Heliyon"},{"key":"2026100208420169000_cit12","doi-asserted-by":"publisher","first-page":"2848","DOI":"10.3390\/ijms24032848","article-title":"The regulation\nof cyclins and cyclin-dependent kinases in the development of gastric\ncancer","volume":"24","author":"Javed","year":"2023","journal-title":"Int. J. Mol. Sci."},{"issue":"Pt 2","key":"2026100208420169000_cit13","doi-asserted-by":"publisher","first-page":"148957","DOI":"10.1016\/j.ijbiomac.2025.148957","article-title":"The dual\nrole of cyclin D1: Unraveling its tumor-promoting mechanisms and opportunities\nfor therapeutics","volume":"333","author":"Taheri","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"issue":"3","key":"2026100208420169000_cit14","doi-asserted-by":"publisher","first-page":"63","DOI":"10.3390\/cancers10030063","article-title":"Kinases and Cancer","volume":"10","author":"Cicenas","year":"2018","journal-title":"Cancers"},{"issue":"4","key":"2026100208420169000_cit15","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1055\/a-1989-1856","article-title":"Protein kinases: Role of their dysregulation in carcinogenesis,\nidentification\nand inhibition","volume":"73","author":"Sarkar","year":"2023","journal-title":"Drug Res."},{"issue":"1","key":"2026100208420169000_cit16","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/s43556-022-00110-2","article-title":"Targeting the PI3K\/AKT\/mTOR and RAF\/MEK\/ERK\npathways for cancer therapy","volume":"3","author":"Li","year":"2022","journal-title":"Mol Biomed."},{"issue":"3","key":"2026100208420169000_cit17","doi-asserted-by":"publisher","first-page":"144","DOI":"10.33696\/immunology.3.091","article-title":"Ca2+\/calmodulin-dependent\nProtein Kinases in Leukemia Development","volume":"3","author":"Cui","year":"2021","journal-title":"J.\nCell Immunol."},{"issue":"1","key":"2026100208420169000_cit18","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1186\/s12935-021-02030-7","article-title":"The dysregulated expression\nand functional effect of CaMK2 in cancer","volume":"21","author":"He","year":"2021","journal-title":"Cancer\nCell Int."},{"issue":"3","key":"2026100208420169000_cit19","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1042\/EBC20240011","article-title":"CaMKK2: bridging the\ngap between Ca2+ signaling and energy-sensing","volume":"68","author":"McAloon","year":"2024","journal-title":"Essays Biochem."},{"issue":"5","key":"2026100208420169000_cit20","doi-asserted-by":"publisher","first-page":"2687","DOI":"10.1021\/acs.jproteome.1c00008","article-title":"Molecular Profiling Associated with Calcium\/Calmodulin-Dependent\nProtein Kinase Kinase 2 (CAMKK2)-Mediated Carcinogenesis in Gastric\nCancer","volume":"20","author":"Najar","year":"2021","journal-title":"J. Proteome Res."},{"issue":"19","key":"2026100208420169000_cit21","doi-asserted-by":"publisher","first-page":"11025","DOI":"10.3390\/ijms231911025","article-title":"Molecular Mechanisms\nUnderlying Ca(2+)\/Calmodulin-Dependent\nProtein Kinase Kinase Signal Transduction","volume":"23","author":"Tokumitsu","year":"2022","journal-title":"Int.\nJ. Mol. Sci."},{"issue":"10","key":"2026100208420169000_cit22","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1016\/j.tem.2016.06.001","article-title":"The Ca(2+)\/Calmodulin\/CaMKK2\nAxis:\nNature\u2019s Metabolic CaMshaft","volume":"27","author":"Marcelo","year":"2016","journal-title":"Trends Endocrinol.\nMetab."},{"issue":"2","key":"2026100208420169000_cit23","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.molmed.2012.12.004","article-title":"CaMKK2: a\nnovel target for shaping the androgen-regulated tumor ecosystem","volume":"19","author":"Racioppi","year":"2013","journal-title":"Trends Mol. 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