HIF-α Promotes Chronic Myelogenous Leukemia Cell Proliferation by Upregulating p21 Expression

Abstract

We sought to determine the expression levels of hypoxia-inducible factor-1α (HIF-1α) in the bone marrow chronic myelogenous leukemia (CML) patients. We also tried to determine the roles HIF-1α in the proliferation of CML cells by small interfering RNA (siRNA) knockdown. Real-time PCR was performed to determine the expression levels of HIF-1α in the bone marrows of CML patients and healthy volunteers. HIF-1α knockdown by siRNA in K562 cells was confirmed by RT-PCR. Proliferation and colony formation of the treated cells were determined by CCK8 after HIF-1α knockdown. RT-PCR and western blotting were performed to detect mRNA and protein levels of p21 and p53 in K562 cells. HIF-1α mRNA expression in the bone marrow of CML patients was significantly higher than that in the control, which was statistically significant (P < 0.05). HIF-1α knockdown dramatically reduced the proliferation of K562 cells, which was also statistically significant (P < 0.05). HIF-1α knockdown markedly reduced the colony formation ability of K562 cells, which was also statistically significant (P < 0.05). The mRNA and protein expression of p21 were significantly reduced in K562 cell after HIF-1α knockdown with affecting the mRNA and protein levels of p53. HIF-α promotes chronic CML cell proliferation by up-regulating p21 expression.

Altered intracellular signaling by imatinib increases the anti‐cancer effects of tyrosine kinase inhibitors in chronic myelogenous leukemia cells

“…Also, lactate production remained low when cells were exposed to 0.1 μmol/L IM for 4 weeks (Figure B). Furthermore, we observed reduced expression of HIF‐1α protein, which contributes to increased glycolysis and proliferation of cancer cells, and reduced expression of mRNA encoding glycolytic enzymes hexokinase 2 and lactate dehydrogenase A in K562‐IM3w cells (Figure C,D). Inhibiting glycolysis using 2‐deoxy‐ d ‐glucose increases the efficacy of several anti‐cancer agents; however, inhibiting glycolysis in K562 cells using 2‐deoxy‐ d ‐glucose did not increase their sensitivity to IM (Figure E), despite marked inhibition of glycolysis (Figure ).…”

Hypoxia and Hypoxia-Inducible Factors in Leukemias

“…Overexpression of HIF-1alpha in leukemia has been suggested as a marker of poor prognosis and chemotherapy outcomes ( 78 – 81 ). Elevated levels of HIF-1alpha are reported, in the majority of studies, in AML ( 79 , 82 – 84 ), acute promyelocytic leukemia (APL) ( 85 ), ALL ( 82 ), and CML ( 86 , 87 ). Disease severity and survival have been shown to be influenced by HIF-1alpha levels, in AML and myelodysplastic syndromes ( 84 , 88 , 89 ); the protein expression of HIF-2alpha, usually absent in normal cells, has been observed in both AML and ALL, but has not been correlated with outcome ( 82 , 90 , 91 ).…”

Resveratrol Inhibits Proliferation and Promotes Apoptosis of Keloid Fibroblasts by Targeting HIF-1α

“…HIF-1α was identified as an effector in increase of cell number, inhibition of proliferation in various cell types given inadequate supply of oxygen [21][22][23][24]. Since we observed the hypoxia-induced inhibition of apoptosis and enhancement of proliferation was attenuated by resveratrol, we suspected this reversal may be related to HIF-1α, an established marker of cellular response to hypoxia.…”