ALDOA inhibits cell cycle arrest induced by DNA damage via the ATM-PLK1 pathway in pancreatic cancer cells

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.

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

“…In the case of ATM, it may be that the binding of ALDOA, directly to ATM or to an ATM-associated complex, may promote the destabilization of the ATM dimer and promote the autophosphorylation and subsequent activation of each ATM molecule. Although ALDOA has not been implicated in regulating ATM activity previously, in contrast to our data, a previous study found that overexpression of ALDOA led to downregulation of ATM levels in pancreatic cancer cells, suggesting that ALDOA levels need to be tightly regulated to avoid disruption of DNA repair pathways 47 .…”

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

“…Previous studies have indicated that oncogenes enhance glycolysis by increasing the expression of specific glucose transporters and glycolytic enzymes, promoting the proliferation of cancer cells. Studies have shown that ALDOA is included in the pathological processes of various cancers 9 , 12 , 13 , 18 .…”

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

“…Overexpression of Aldoa induced p53-dependent apoptosis in xenograft tumors in mice [ 40 ]. In pancreatic cancer cells, Aldoa inhibited DNA repair and in consequence promoted cancer development [ 41 ]. The hypothesis that anti-apoptotic mechanisms and those related to DNA repair are involved in TAM action in rat ovaries during the CPA treatment seems to be justified.…”