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Gene expression profile induced by arsenic trioxide in chronic lymphocytic
leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and
regulation of matrix metalloproteinase-9
#MMPMID27829220
Amigo-Jiménez I
; Bailón E
; Aguilera-Montilla N
; García-Marco JA
; García-Pardo A
Oncotarget
2016[Dec]; 7
(50
): 83359-83377
PMID27829220
show ga
CLL remains an incurable disease in spite of the many new compounds being tested.
Arsenic trioxide (ATO) induces apoptosis in all CLL cell types and could
constitute an efficient therapy. To further explore this, we have studied the
gene expression profile induced by ATO in CLL cells. ATO modulated many genes,
largely involved in oxidative stress, being HMOX1 the most upregulated gene, also
induced at the protein level. ATO also increased MMP-9, as we previously
observed, both at the mRNA and protein level. Using specific inhibitors, qPCR
analyses, and gene silencing approaches we demonstrate that upregulation of MMP-9
by ATO involved activation of the p38 MAPK/AP-1 signaling pathway. Moreover, gene
silencing HMOX1 or inhibiting HMOX1 activity enhanced p38 MAPK phosphorylation
and c-jun expression/activation, resulting in transcriptional upregulation of
MMP-9. Overexpression of HMOX1 or enhancement of its activity, had the opposite
effect. Cell viability analyses upon modulation of HMOX1 expression or activity
demonstrated that HMOX1 had a pro-apoptotic role and enhanced the cytotoxic
effect of ATO in CLL cells. We have therefore identified a new mechanism in which
HMOX1 plays a central role in the response of CLL cells to ATO and in the
regulation of the anti-apoptotic protein MMP-9. Thus, HMOX1 arises as a new
therapeutic target in CLL and the combination of HMOX1 modulators with ATO may
constitute an efficient therapeutic strategy in CLL.
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