Cholesterol Starvation Induces Differentiation of Human Leukemia HL-60 Cells

Abstract

Cholesterol metabolism is particularly active in malignant, proliferative cells, whereas cholesterol starvation has been shown to inhibit cell proliferation. Inhibition of enzymes involved in cholesterol biosynthesis at steps before the formation of 7-dehydrocholesterol has been shown to selectively affect cell cycle progression from G 2 phase in human promyelocytic HL-60 cells. In the present work, we explored whether cholesterol starvation by culture in cholesterol-free medium and treatment with different distal cholesterol biosynthesis inhibitors induces differentiation of HL-60 cells. Treatment with SKF 104976, an inhibitor of lanosterol 14-A demethylase, or with zaragozic acid, which inhibits squalene synthase, caused morphologic changes alongside respiratory burst activity and expression of cluster of differentiation antigen 11c (CD11c) but not cluster of differentiation antigen 14. These effects were comparable to those produced by all-trans retinoic acid, which induces HL-60 cells to differentiate following a granulocyte lineage. In contrast, they differed from those produced by vitamin D 3 , which promotes monocyte differentiation. The specificity of the response was confirmed by addition of cholesterol to the culture medium. Treatment with PD 98059, an inhibitor of extracellular signal-regulated kinase, abolished both the activation of NADPH oxidase and the expression of the CD11c marker. In sharp contrast, BM 15766, which inhibits sterol # 7 -reductase, failed to induce differentiation or arrest cell proliferation. These results show that changes in the sterol composition may trigger a differentiation response and highlight the potential of cholesterol pathway inhibition as a possible tool for use in cancer therapy. [Cancer Res 2007;67(7):3379-86]

Metabolic factors and blood cancers among 578,000 adults in the metabolic syndrome and cancer project (Me-Can)

“…In contrast to a meta-analysis of cohort studies 24 , we found no association between BMI and AML. Our findings of an inverse association between cholesterol and myeloid neoplasms in particular AML is consistent with results from experimental studies 25,26 . Reverse causation is thought to contribute to the inverse association 27 since time-dependent associations have been reported between cholesterol and cancer risk 28 .…”

Cholesterol synthesis-related enzyme oxidosqualene cyclase is required to maintain self-renewal in primary erythroid progenitors

“…The hypothesis of cholesterol synthesis involvement in the self‐renewal/differentiation balance is in agreement with previous studies pointing out a link between cholesterol homeostasis and differentiation. First, it was shown that both HMG‐CoA reductase inhibition (31) and, more specifically, cholesterol starvation (32) induce differentiation of human leukaemia HL‐60 cells. Moreover, hypercholesterolaemia has been reported to result in blockage of erythroid differentiation (33).…”

Cholesterol and 27-hydroxycholesterol promote thyroid carcinoma aggressiveness

“…To meet these needs, these deregulated cells are able to promote two strategies cholesterol uptake from the bloodstream and de novo cholesterol biosynthesis 1–4 . In this context, hypercholesterolemia has been identified as a risk factor in the development or malignant drift of some solid tumors, such as in breast, colon, and prostate cancer 5–8 . In contrast, the inhibition of the cholesterol synthesis pathway can activate the mechanisms of cell differentiation 9 .…”