Acquired resistance of leukemic cells to AraC is associated with the upregulation of aldehyde dehydrogenase 1 family member A2

Abstract

The elucidation of drug resistance mechanisms is important in the development of clinical therapies for the treatment of leukemia. To study the drug resistance mechanisms, protein expression profiles of 1-β-D-arabinofuranosylcytosine (AraC)-sensitive K562 (K562S) cells and AraC-resistant K562 (K562AC) cells were compared using two-dimensional fluorescence difference gel electrophoresis. In a comparison of protein expression profiles, 2073 protein spots were found to be altered, and 15 proteins of them were remarkably altered. These proteins were identified by mass spectrometry. The most differently expressed proteins were aldehyde dehydrogenase 1 family member A2 (ALDH1A2) and vimentin. Both proteins were verified using reverse transcriptase polymerase chain reaction and Western blot analysis. ALDH1A2 protein was found to be effective in AraC resistance. ALDH1A2 knock-down induced sensitivity to AraC treatment in K562AC cells, and ALDH1A2 overexpressed K562S cells acquired the AraC resistance. Furthermore, the findings also suggest that ALDH1A2 expression is increased after the appearance of AraC resistance in clinical cases. These results will be helpful in understanding the mechanism of AraC resistance.

Discovery of microarray-identified genes associated with ovarian cancer progression

“…ALDH1A2 is identified to be a candidate TSG in prostate cancer whose expression is induced by DNA demethylation, which is reduced in prostate tumors compared with normal prostate, and negatively correlated with tumor-free survival (57). A further study indicate that ALDH1A2 is involved in apoptosis in bladder cancer cells (58), and has significant effects on cell proliferation and drug resistance in leukemia (59,60) and lung cancer cell lines (59). A more recent study indicate that high expression of ALDH1A2 is implicated in conveying tolerance to cisplatin in the three malignant pleural mesothelioma cell lines (61).…”

Chemotherapy selection pressure alters sphingolipid composition and mitochondrial bioenergetics in resistant HL-60 cells

“…Prominent mechanisms of drug resistance in AML include diminished dnr intracellular retention directed by transporters such as P-gp, whereas Ara-C resistance is often linked to enhanced ALDH1A2 (36) and reduced capacity of the activating enzyme deoxycytidine kinase and overexpression of the inactivating 5′-nucleotidase, cytoplasmic 5′-nucleotidase II (40)(41)(42). Whereas research on chemotherapy-induced apoptosis and downstream signaling has made great strides, the initial signaling events in chemotherapy action remain unclear.…”

Aldehyde Dehydrogenases: Not Just Markers, but Functional Regulators of Stem Cells

“…ALDH expression by tumor cells imparts resistance to cytotoxic drugs, such as cyclophosphamide and its active derivative hydroperoxycyclophosphamide (4-HC) [98, 99], doxorubicin [100], cisplatin [101], arabinofuranosyl cytidine (Ara-C) [102], and dacarbazine [96], among others. Cancer cells expressing high levels of ALDH can develop drug resistance of the ALDH-specific activity that catabolyzes a particular drug through oxidation of the specific aldehyde group of the drug [102].…”