ALDOA Inhibits Cell Cycle Arrest Induced by DNA Damage Via the ATM-PLK1 Pathway in Pancreatic Cancer Cells

Overview

Journal Cancer Cell Int

Publisher Biomed Central

Date 2021 Sep 27

PMID 34565365

Citations 6

Authors

Haidi Chen

Zeng Ye

Xiaowu Xu

Yi Qin

Changfeng Song

Guixiong Fan

Haifeng Hu

Yuheng Hu

Xianjun Yu

Wensheng Liu

Shunrong Ji

Wenyan Xu

Affiliations

Soon will be listed here.

Abstract

Background: ALDOA is a glycolytic enzyme found mainly in developing embryos, adult muscle and various malignant tumours, including pancreatic tumours. Our previous study revealed that ALDOA, an oncogene, can promote the proliferation and metastasis of pancreatic tumours. Furthermore, ALDOA could predict poor prognosis in patients with pancreatic tumours.

Methods: IHC analysis of PDAC tissues was conducted. Western blotting, PCR, cellular IF experiments and cell cycle assessment were conducted utilizing cell lines. GSEA and KEGG pathway analysis were used to identify potential downstream pathways.

Results: To explore the effects of ALDOA on the occurrence and development of pancreatic tumours, we analysed the RNA sequencing results and found that ALDOA could inhibit the DDR. Under normal circumstances, when DNA is damaged, initiation of the DDR causes cell cycle arrest, DNA repair or cell apoptosis. Further experiments showed that ALDOA could inhibit DNA repair and reverse cell cycle arrest induced by DNA damage so that DNA damage persisted to promote the occurrence and progression of cancer.

Conclusions: Regarding the molecular mechanism, we found that ALDOA inhibited the DDR and improved activation of the cell cycle checkpoint PLK1 by suppressing ATM, which promotes tumour cell progression. Consequently, ALDOA has a profound effect on pancreatic cancer development.

Citing Articles

Molecular mechanisms of m6A modifications regulating tumor radioresistance.

Shen R, Jiang Z, Wang H, Zheng Z, Jiang X Mol Med. 2025; 31(1):64.

PMID: 39972266 PMC: 11837317. DOI: 10.1186/s10020-025-01121-9.

ATM, BLM, and CDH1 gene co-mutations in a high-grade endometrial stromal sarcoma patient with multiple abdominal cavity metastases: a case report and literature review.

Li N, Yan Y, Li Y, Yang Y, Dai C, Li N BMC Geriatr. 2024; 24(1):603.

PMID: 39009979 PMC: 11247777. DOI: 10.1186/s12877-024-05201-z.

Prognosis significance and potential association between ALDOA and AKT expression in colorectal cancer.

Xu M, Xi S, Li H, Xia Y, Mei G, Cheng Z Sci Rep. 2024; 14(1):6488.

PMID: 38499636 PMC: 10948905. DOI: 10.1038/s41598-024-57209-5.

The fructose-bisphosphate, Aldolase A (ALDOA), facilitates DNA-PKcs and ATM kinase activity to regulate DNA double-strand break repair.

Sobanski T, Suraweera A, Burgess J, Richard I, Cheong C, Dave K Sci Rep. 2023; 13(1):15171.

PMID: 37704669 PMC: 10499815. DOI: 10.1038/s41598-023-41133-1.

Tamoxifen decreases ovarian toxicity without compromising cancer treatment in a rat model of mammary cancer.

Nynca A, Swigonska S, Ruszkowska M, Sadowska A, Orlowska K, Molcan T BMC Genomics. 2023; 24(1):325.

PMID: 37312040 PMC: 10265842. DOI: 10.1186/s12864-023-09423-0.

References

Zhang F, Lin J, Zuo X, Zhuang Y, Hong C, Zhang G . Elevated transcriptional levels of aldolase A (ALDOA) associates with cell cycle-related genes in patients with NSCLC and several solid tumors. BioData Min. 2017; 10:6. PMC: 5297095. DOI: 10.1186/s13040-016-0122-4. View

Strebhardt K, Ullrich A . Targeting polo-like kinase 1 for cancer therapy. Nat Rev Cancer. 2006; 6(4):321-30. DOI: 10.1038/nrc1841. View

Mamczur P, Gamian A, Kolodziej J, Dziegiel P, Rakus D . Nuclear localization of aldolase A correlates with cell proliferation. Biochim Biophys Acta. 2013; 1833(12):2812-2822. DOI: 10.1016/j.bbamcr.2013.07.013. View

Falck J, Coates J, Jackson S . Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature. 2005; 434(7033):605-11. DOI: 10.1038/nature03442. View

Ritterson Lew C, Tolan D . Targeting of several glycolytic enzymes using RNA interference reveals aldolase affects cancer cell proliferation through a non-glycolytic mechanism. J Biol Chem. 2012; 287(51):42554-63. PMC: 3522257. DOI: 10.1074/jbc.M112.405969. View

Oparina N, Snezhkina A, Sadritdinova A, Veselovskii V, Dmitriev A, Senchenko V . [Differential expression of genes that encode glycolysis enzymes in kidney and lung cancer in humans]. Genetika. 2014; 49(7):814-23. DOI: 10.7868/s0016675813050111. View

Jazayeri A, Falck J, Lukas C, Bartek J, Smith G, Lukas J . ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol. 2005; 8(1):37-45. DOI: 10.1038/ncb1337. View

Chang Y, Chan Y, Chang W, Lin Y, Yang C, Su C . Feedback regulation of ALDOA activates the HIF-1α/MMP9 axis to promote lung cancer progression. Cancer Lett. 2017; 403:28-36. DOI: 10.1016/j.canlet.2017.06.001. View

Zitouni S, Nabais C, Jana S, Guerrero A, Bettencourt-Dias M . Polo-like kinases: structural variations lead to multiple functions. Nat Rev Mol Cell Biol. 2014; 15(7):433-52. DOI: 10.1038/nrm3819. View

10.

Gaul L, Mandl-Weber S, Baumann P, Emmerich B, Schmidmaier R . Bendamustine induces G2 cell cycle arrest and apoptosis in myeloma cells: the role of ATM-Chk2-Cdc25A and ATM-p53-p21-pathways. J Cancer Res Clin Oncol. 2007; 134(2):245-53. DOI: 10.1007/s00432-007-0278-x. View

11.

Smits V, Klompmaker R, Arnaud L, Rijksen G, Nigg E, Medema R . Polo-like kinase-1 is a target of the DNA damage checkpoint. Nat Cell Biol. 2000; 2(9):672-6. DOI: 10.1038/35023629. View

12.

Ma D, Chen X, Zhang P, Zhang H, Wei L, Hu S . Upregulation of the ALDOA/DNA-PK/p53 pathway by dietary restriction suppresses tumor growth. Oncogene. 2017; 37(8):1041-1048. DOI: 10.1038/onc.2017.398. View

13.

Liu Z, Sun Q, Wang X . PLK1, A Potential Target for Cancer Therapy. Transl Oncol. 2016; 10(1):22-32. PMC: 5124362. DOI: 10.1016/j.tranon.2016.10.003. View

14.

Marechal A, Zou L . DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol. 2013; 5(9). PMC: 3753707. DOI: 10.1101/cshperspect.a012716. View

15.

Li D, Xie K, Wolff R, Abbruzzese J . Pancreatic cancer. Lancet. 2004; 363(9414):1049-57. DOI: 10.1016/S0140-6736(04)15841-8. View

16.

Ji S, Zhang B, Liu J, Qin Y, Liang C, Shi S . ALDOA functions as an oncogene in the highly metastatic pancreatic cancer. Cancer Lett. 2016; 374(1):127-135. DOI: 10.1016/j.canlet.2016.01.054. View

17.

Gheghiani L, Wang L, Zhang Y, Moore X, Zhang J, Smith S . PLK1 Induces Chromosomal Instability and Overrides Cell-Cycle Checkpoints to Drive Tumorigenesis. Cancer Res. 2020; 81(5):1293-1307. PMC: 8026515. DOI: 10.1158/0008-5472.CAN-20-1377. View

18.

Lee J, Paull T . ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science. 2005; 308(5721):551-4. DOI: 10.1126/science.1108297. View

19.

Vincent A, Herman J, Schulick R, Hruban R, Goggins M . Pancreatic cancer. Lancet. 2011; 378(9791):607-20. PMC: 3062508. DOI: 10.1016/S0140-6736(10)62307-0. View

20.

Fu H, Gao H, Qi X, Zhao L, Wu D, Bai Y . Aldolase A promotes proliferation and G/S transition via the EGFR/MAPK pathway in non-small cell lung cancer. Cancer Commun (Lond). 2018; 38(1):18. PMC: 5993145. DOI: 10.1186/s40880-018-0290-3. View