{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nAldolase A (ALDOA) is a central glycolytic enzyme that catalyzes the reversible conversion of fructose‑1,6‑bisphosphate into glyceraldehyde‑3‑phosphate and dihydroxyacetone phosphate, thereby sustaining energy production. However, beyond its canonical metabolic function, ALDOA has emerged as a multifunctional “moonlighting” protein that integrates cell metabolism with cytoskeletal dynamics, regulating cell shape and migration. For example, PI3K‐dependent signals have been shown to trigger Rac activation, leading to the release of F‑actin–bound ALDOA and consequent increases in its activity, which links energy uptake with cytoskeletal reorganization (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "]). In addition, ALDOA participates in processes such as keratinocyte migration, underscoring its involvement in normal cell physiology (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "])."}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn multiple cancer types, ALDOA overexpression has been correlated with enhanced malignancy, metastasis, and poor clinical outcomes. In lung squamous cell carcinoma, for instance, high ALDOA expression is associated with increased metastatic potential, while in pancreatic cancer, its upregulation—often in response to transforming growth factor‑β—drives proliferation, metastasis, and epithelial–mesenchymal transition (EMT) via modulations in key regulators such as c‑Myc, HIF‑1α, and NRF2 (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "]). Similarly, in lung cancer, ALDOA promotes metastasis by affecting hypoxia signaling and matrix metalloproteinase‑9 (MMP9) activation (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "]), while its direct interaction with γ‑actin has been implicated in facilitating cancer cell invasion—a mechanism recently targeted pharmacologically using raltegravir (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "]). Additional studies in renal cell carcinoma and cholangiocarcinoma have also shown that ALDOA contributes to tumor progression through EMT modulation and related signaling pathways (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "]). In cervical adenocarcinoma, ALDOA overexpression correlates with lymph node metastasis and reduced overall survival, acting in part via a positive feedback loop with HIF‑1α (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "]), and in colon cancer, its upregulation—often driven by a POU2F1‑ALDOA axis—enhances metabolic reprogramming and resistance to chemotherapeutic agents (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "])."}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond driving glycolysis and cytoskeletal rearrangements that underlie tumor aggressiveness, ALDOA also exerts regulatory actions on cell survival and stress responses. Under dietary restriction, for instance, ALDOA expression increases in xenograft tumors where it physically associates with DNA‑PK, leading to p53 phosphorylation and activation—a mechanism that can suppress tumor growth in the presence of functional p53 but may conversely promote tumorigenesis when p53 is compromised (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "]). Moreover, recent findings indicate that in cancer cells, ALDOA’s non‑catalytic functions—particularly its ability to interact with and modulate the F‑actin cytoskeleton—are critical in regulating reactive oxygen species production, calcium levels, and apoptotic pathways, thereby maintaining cell survival independent of its enzymatic activity (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "]). Collectively, these studies establish ALDOA as a multifaceted protein whose dysregulation not only reprograms energy metabolism but also contributes to EMT, metastasis, and chemoresistance in diverse malignancies, marking it as a promising prognostic biomarker and therapeutic target (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "])."}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sha Du, Zhuzhu Guan, Lihong Hao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fructose-bisphosphate aldolase a is a potential metastasis-associated marker of lung squamous cell carcinoma and promotes lung cell tumorigenesis and migration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0085804"}], "href": "https://doi.org/10.1371/journal.pone.0085804"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24465716"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24465716"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Hai Hu, Ashish Juvekar, Costas A Lyssiotis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2015.12.042"}], "href": "https://doi.org/10.1016/j.cell.2015.12.042"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26824656"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26824656"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Takumi Tochio, Hiroshi Tanaka, Satoru Nakata, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fructose-1,6-bisphosphate aldolase A is involved in HaCaT cell migration by inducing lamellipodia formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Dermatol Sci (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jdermsci.2010.02.012"}], "href": "https://doi.org/10.1016/j.jdermsci.2010.02.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20362419"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20362419"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Shunrong Ji, Bo Zhang, Jiang Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ALDOA functions as an oncogene in the highly metastatic pancreatic cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Lett (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.canlet.2016.01.054"}], "href": "https://doi.org/10.1016/j.canlet.2016.01.054"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26854714"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26854714"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Yu-Chan Chang, Yung-Chieh Chan, Wei-Ming Chang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Feedback regulation of ALDOA activates the HIF-1α/MMP9 axis to promote lung cancer progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Lett (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.canlet.2017.06.001"}], "href": "https://doi.org/10.1016/j.canlet.2017.06.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28610954"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28610954"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yu-Chan Chang, Jean Chiou, Yi-Fang Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Therapeutic Targeting of Aldolase A Interactions Inhibits Lung Cancer Metastasis and Prolongs Survival."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-18-4080"}], "href": "https://doi.org/10.1158/0008-5472.CAN-18-4080"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31358528"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31358528"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Zhengkai Huang, Yibo Hua, Ye Tian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High expression of fructose-bisphosphate aldolase A induces progression of renal cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.2018.6378"}], "href": "https://doi.org/10.3892/or.2018.6378"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29693182"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29693182"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Zhuo Xu, Guangchao Liu, Meng Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-122-5p Inhibits the Proliferation, Invasion and Growth of Bile Duct Carcinoma Cells by Targeting ALDOA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Physiol Biochem (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000492702"}], "href": "https://doi.org/10.1159/000492702"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30121648"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30121648"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Yuki Saito, Akira Takasawa, Kumi Takasawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aldolase A promotes epithelial-mesenchymal transition to increase malignant potentials of cervical adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cas.14524"}], "href": "https://doi.org/10.1111/cas.14524"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32530543"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32530543"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Ya Peng, Xiayu Li, Minghua Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "New prognosis biomarkers identified by dynamic proteomic analysis of colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biosyst (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1039/c2mb25286d"}], "href": "https://doi.org/10.1039/c2mb25286d"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22996014"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22996014"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jinguan Lin, Longzheng Xia, Linda Oyang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The POU2F1-ALDOA axis promotes the proliferation and chemoresistance of colon cancer cells by enhancing glycolysis and the pentose phosphate pathway activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41388-021-02148-y"}], "href": "https://doi.org/10.1038/s41388-021-02148-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34997215"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34997215"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "D Ma, X Chen, P-Y Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Upregulation of the ALDOA/DNA-PK/p53 pathway by dietary restriction suppresses tumor growth."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2017.398"}], "href": "https://doi.org/10.1038/onc.2017.398"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29084207"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29084207"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Agnieszka Gizak, Janusz Wiśniewski, Paul Heron, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeting a moonlighting function of aldolase induces apoptosis in cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-019-1968-4"}], "href": "https://doi.org/10.1038/s41419-019-1968-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31558701"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31558701"}]}]}]}