Mechanism of HIF-1α-PDK1 signaling system involved in glucose metabolism and drug resistance in acute monocytic leukemia
10.3969/j.issn.1674-8115.2018.11.004
- Author:
Xiao-Wei XU
1
Author Information
1. Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
- Publication Type:Journal Article
- Keywords:
Acute monocytic leukemia;
Hypoxia-inducible factor-1α (HIF-1α);
Multidrug resistance;
Pyruvate dehydrogenase kinase 1 (PDK1)
- From:
Journal of Shanghai Jiaotong University(Medical Science)
2018;38(11):1294-1299
- CountryChina
- Language:Chinese
-
Abstract:
Objective • To investigate the mechanism of HIF-1α-PDK1 signaling system mediated glucose metabolism and drug resistance in acute monocytic leukemia cells. Methods • The expression of pyruvate dehydrogenase kinase 1 (PDK1) mRNA in U937, U937/DNR and acute monocytic leukemia cells was detected by quantitative polymerase chain reaction (qPCR). siRNA HIF-1α plasmid was constructed and transferred to U937 and U937/ DNR cells for 24 h by gene silencing. Cell proliferation inhibition was examined by MTT assay. The level of PDK1 mRNA was detected by qPCR, and the expression of PDK1 and multi-drug resistance gene 1 (MDR1) proteins was detected by Western blotting. Cell membrane potential was measured by flow cytometry using JC-1. Lactic acid level in the culture fluid was determined by blood gas analyzer. Dichloroacetate (DCA) and daunorubicin (DNR) were added to treat U937/DNR and acute monocytic leukemia cells for 24 h, MTT was used to calculate cell proliferation inhibition and Western blotting was used to estimate the expression of PDK1 and MDR1 proteins. Results • PDK1 mRNA was highly expressed in U937, U937/DNR and acute monocytic leukemia cells. Silencing hypoxia-inducible factor-1α (HIF-1α) significantly inhibited the proliferation activity, PDK1 and MDR1 expression and lactic acid production in U937 and U937/DNR cells. DCA could reverse the resistance to DNR in U937/DNR and relapsed acute monocytic leukemia cells. Conclusion • HIF-1α-PDK1 signaling system may regulate glucose metabolism and participate in the drug resistance of acute monocytic leukemia.
