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. 2009 Jul;94(1):32-8.
doi: 10.1016/j.ygeno.2009.03.005. Epub 2009 Apr 5.

Gene expression profiling for nitric oxide prodrug JS-K to kill HL-60 myeloid leukemia cells

Jie Liu  1 , Swati Malavya, Xueqian Wang, Joseph E Saavedra, Larry K Keefer, Erik Tokar, Wei Qu, Michael P Waalkes, Paul J Shami
Affiliations

Gene expression profiling for nitric oxide prodrug JS-K to kill HL-60 myeloid leukemia cells

Jie Liu et al. Genomics. 2009 Jul.

Abstract

The nitric oxide (NO) prodrug JS-K is shown to have anticancer activity. To profile the molecular events associated with the anticancer effects of JS-K, HL-60 leukemia cells were treated with JS-K and subjected to microarray and real-time RT-PCR analysis. JS-K induced concentration- and time-dependent gene expression changes in HL-60 cells corresponding to the cytolethality effects. The apoptotic genes (caspases, Bax, and TNF-alpha) were induced, and differentiation-related genes (CD14, ITGAM, and VIM) were increased. For acute phase protein genes, some were increased (TP53, JUN) while others were suppressed (c-myc, cyclin E). The expression of anti-angiogenesis genes THBS1 and CD36 and genes involved in tumor cell migration such as tissue inhibitors of metalloproteinases, were also increased by JS-K. Confocal analysis confirmed key gene changes at the protein levels. Thus, multiple molecular events are associated with JS-K effects in killing HL-60, which could be molecular targets for this novel anticancer NO prodrug.

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Figures

Figure 1
Figure 1
Effect of JS-K on the expression of apoptosis-related genes. HL-60 cells were treated with 0, 0.25, 0.5, and 1.0 μM JS-K for 24 hr, and total purified RNA was subjected to real-time RT-PCR analysis. Data are mean and SEM (n = 3). *Significantly different from controls, p < 0.05.
Figure 2
Figure 2
Effect of JS-K on the expression of cell differentiation-related genes. HL-60 cells were treated with 0, 0.25, 0.5, and 1.0 μM JS-K for 24 hr, and total purified RNA was subjected to real-time RT-PCR analysis. Data are mean and SEM (n = 3). *Significantly different from controls, p < 0.05.
Figure 3
Figure 3
Effect of JS-K on the expression of acute phase protein genes. HL-60 cells were treated with 0, 0.25, 0.5, and 1.0 μM JS-K for 24 hr, and total purified RNA was subjected to real-time RT-PCR analysis. Data are mean and SEM (n = 3). *Significantly different from controls, p < 0.05.
Figure 4
Figure 4
Effect of JS-K on the expression of anti-angiogenesis-related genes. HL-60 cells were treated with 0, 0.25, 0.5, and 1.0 μM JS-K for 24 hr, and total purified RNA was subjected to real-time RT-PCR analysis. Data are mean and SEM (n = 3). *Significantly different from controls, p < 0.05.
Figure 5
Figure 5
Effect of JS-K on the expression of MMPs and TIMPs. HL-60 cells were treated with 0, 0.25, 0.5, and 1.0 μM JS-K for 24 hr, and total purified RNA was subjected to real-time RT-PCR analysis. Data are mean and SEM (n = 3). *Significantly different from controls, p < 0.05.
Figure 6
Figure 6
Representative confocal image analysis of the expression of caspase-3, CD14, c-myc, and TIMP1. HL-60 cells were treated with 1.0 μM JS-K or leave untreated for 24 hr. Cells were then harvested, fixed, permeabilized, and incubated with specific primary antibodies and fluorescence labelled secondary antibodies for confocal imaging as detailed in Methods.
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