{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:07:03Z","timestamp":1790053623764,"version":"4.0.1"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>\n                    The microenvironment of many solid tumors is acidic (pH 6.5-6.9) due to hypoxia and enhanced glycolytic metabolism and has been implicated in tumor progression and therapeutic resistance. However, the mechanisms by which pancreatic cancer cells adapt to extracellular acidosis and maintain survival under acidic stress remain incompletely understood. This study aimed to investigate the effects of extracellular acidosis on pancreatic cancer cell proliferation, apoptosis, cell cycle regulation, and intracellular signaling. Human pancreatic cancer cell lines PK-59 and MIA-PaCa-2 were cultured under acidic conditions (pH 6.9). Proliferation, cell cycle phase distribution, apoptosis, and intracellular signaling were assessed using cell growth assays, WST-8 assays, flow cytometry, and western blotting. Pharmacological inhibition of Akt and ERK1\/2 was performed to evaluate their functional roles under acidic conditions. Under acidic conditions, both cell lines appeared to show reduced proliferation, an increased G\n                    <jats:sub>0<\/jats:sub>\n                    \/G\n                    <jats:sub>1<\/jats:sub>\n                    population, decreased Cyclin D1 and CDK4\/6 expression, and attenuated ERK1\/2 phosphorylation. No apparent increase in apoptosis was observed. Acidic conditions also appeared to be associated with increased Akt phosphorylation and changes in apoptosis-related proteins, including decreased Bad and Bax and increased Bcl-xL. Pharmacological Akt inhibition under acidic conditions appeared to be accompanied by an increased apoptotic population together with increased Bad and Bax and decreased Bcl-xL expression. These observations may suggest an association between Akt signaling and survival-related cellular responses under acidic conditions; however, they do not establish a causal requirement for Akt signaling or a causal relationship between the observed protein changes and apoptosis. ERK1\/2 inhibition appeared to be associated mainly with changes in cell cycle phase distribution and related protein expression, whereas its effects on apoptosis appeared to vary between the two cell lines. Collectively, these findings may be consistent with differential changes in proliferation-associated and survival-associated signaling under extracellular acidosis, although the functional relationships among these changes remain uncertain. The present findings were obtained exclusively\n                    <jats:italic>in vitro<\/jats:italic>\n                    and do not establish pathway-specific causality, therapeutic efficacy, or immediate clinical applicability. Further studies using complementary mechanistic approaches, appropriate\n                    <jats:italic>in vivo<\/jats:italic>\n                    models, and patient-derived systems will be required to determine the biological and clinical relevance of these observations.\n                  <\/jats:p>","DOI":"10.3389\/fonc.2026.1889708","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T04:26:43Z","timestamp":1790051203000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Acidic microenvironment promotes pancreatic cancer cell survival via Akt phosphorylation-mediated suppression of apoptosis"],"prefix":"10.3389","volume":"16","author":[{"given":"Raito","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Laboratory of Clinical and Translational Physiology, Kyoto Pharmaceutical University","place":["Kyoto, 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