Cyclopamine and jervine induce COX-2 overexpression in human erythroleukemia cells but only cyclopamine has a pro-apoptotic effect

doi:10.1016/j.yexcr.2013.01.014

Experimental Cell Research

Volume 319, Issue 7, 15 April 2013, Pages 1043-1053

https://doi.org/10.1016/j.yexcr.2013.01.014 Get rights and content

Abstract

Erythroleukemia is generally associated with a very poor response and survival to current available therapeutic agents. Cyclooxygenase-2 (COX-2) has been described to play a crucial role in the proliferation and differentiation of leukemia cells, this enzyme seems to play an important role in chemoresistance in different cancer types. Previously, we demonstrated that diosgenin, a plant steroid, induced apoptosis in HEL cells with concomitant COX-2 overexpression. In this study, we investigated the antiproliferative and apoptotic effects of cyclopamine and jervine, two steroidal alkaloids with similar structures, on HEL and TF1a human erythroleukemia cell lines and, for the first time, their effect on COX-2 expression. Cyclopamine, but not jervine, inhibited cell proliferation and induced apoptosis in these cells. Both compounds induced COX-2 overexpression which was responsible for apoptosis resistance. In jervine-treated cells, COX-2 overexpression was NF-κB dependent. Inhibition of NF-κB reduced COX-2 overexpression and induced apoptosis. In addition, cyclopamine induced apoptosis and COX-2 overexpression via PKC activation. Inhibition of the PKC pathway reduced both apoptosis and COX-2 overexpression in both cell lines. Furthermore, we demonstrated that the p38/COX-2 pathway was involved in resistance to cyclopamine-induced apoptosis since p38 inhibition reduced COX-2 overexpression and increased apoptosis in both cell lines.

Highlights

► Cyclopamine alone but not jervine induces apoptosis in human erythroleukemia cells. ► Cyclopamine and jervine induce COX-2 overexpression. ► COX-2 overexpression is implicated in resistance to cyclopamine-induced apoptosis. ► Apoptotic potential of jervine is restrained by NF-κB pathway activation. ► PKC is involved in cyclopamine-induced apoptosis and COX-2 overexpression.

Introduction

Erythroleukemia is a subtype of acute myeloid leukemia (AML), which is the most common form of acute leukemia in adults [1]. According to the World Health Organization, erythroleukemia is classified into three subgroups: (1) leukemia with multi-lineage dysplasia, (2) therapy-related AML and myelodysplastic syndromes and (3) acute erythroid leukemia subdivided in erythroleukemia (erythroid/myeloid) and pure erythroid leukemia [2].

Erythroleukemia is generally associated with a very poor response and survival to current available therapeutic agents [3]. During the last years, different approaches have been developed in order to identify new chemical or natural products that can halt the proliferation of erythroleukemia cells by inducing cell cycle arrest, apoptosis or differentiation [4], [5].

Several studies reported a role for arachidonic acid (AA) metabolism in many biological processes including cell proliferation, apoptosis and differentiation in many cancer types. Once released from phospholipid membranes, AA is converted into various prostanoids by cyclooxygenases (COX) [6], [7], [8]. Two isoforms of COX, COX-1 and COX-2, have been identified: COX-1 has been purported to be a constitutive enzyme expressed in different tissues and maintains the physiological level of prostaglandins while modulating diverse cell processes such as cell proliferation, angiogenesis and platelet aggregation whereas COX-2 has been considered as inducible by different agents like proinflammatory cytokines, hormones and tumor promoters [9]. COX-2 is overexpressed in numerous tumors including colorectal, breast, pancreatic and lung cancer, and in various hematological diseases [6], [10], [11], [12], [13].

Previously, we demonstrated that diosgenin, a plant steroid, induced apoptosis in HEL cells with concomitant COX-2 overexpression [14]. The effect of several compounds with a close structure to diosgenin such as tomatidine (Fig. 1) were tested in different cancer cell lines [15]. Tomatidine also has a structure similar to jervine ((3β,23β)-17,23-epoxy-3-hydroxyveratraman-11-one) and cyclopamine (11-deoxojervine), two steroidal alkaloids, extracted from Veratrum californicum that are able to induce apoptosis in leukemia cells [16].

In this study, we investigated the antiproliferative and apoptotic effect of cyclopamine and jervine (Fig. 1) on HEL and TF1a human erythroleukemia cell lines and, for the first time, their effect on COX-2 expression in these cells. The only difference between these two compounds is the presence of a ketone function on C11 in jervine. To our knowledge, jervine has never been reported to have a proapoptotic effect in contrast to cyclopamine. Despite their similar structures, we showed that cyclopamine, but not jervine, induced apoptosis in HEL and TF1a cell lines. However, both compounds induced COX-2 overexpression. Then, to understand the mechanisms implicated in the different effect of cyclopamine and jervine, we studied intracellular signaling pathways.

Section snippets

Materials

RPMI 1640 medium, fetal calf serum (FCS) and penicillin streptomycin were supplied by Gibco BRL (Cergy Pontoise, France). Jervine and cyclopamine, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), human monoclonal antibody against β-actin and chelerythrine were purchased from Sigma Aldrich (Saint Quentin Fallavier, France).

Anti-human poly-ADP-ribose polymerase (PARP) monoclonal antibody and anti-human phospho-Akt (Thr 308) antibody were purchased from Santa Cruz Biotechnology

Cyclopamine but not jervine inhibited the HEL and TF1a cell growth

The antiproliferative effect of cyclopamine or jervine (10–80 μM) on HEL and TF1a cells was determined after 24–96 h by MTT (data not shown). Cyclopamine proved to have strong antiproliferative effect on both cell lines from 40 μM, whereas no antiproliferative effect was observed with jervine at tested concentrations. As shown in Fig. 2A, 40 μM cyclopamine inhibited cell proliferation starting at 48 h for HEL and 72 h for TF1a cells. Jervine did not inhibit cell proliferation at 40 μM in both cell

Discussion

Plants have been a prime source of highly effective conventional drugs for the treatment of many forms of cancer. In recent years, cyclopamine and jervine, two steroidal alkaloids extracted from plants, were investigated in several studies for their antitumor activity [31], [32]. In the present study, we examined the effects of cyclopamine and jervine on apoptosis, COX-2 expression and upstream signaling pathways in human erythroleukemia cell lines HEL and TF1a.

As previously described,

Conclusions

Our findings reveal key elements in the signal transduction pathways that mediate apoptosis and resistance to apoptosis with cyclopamine and jervine in erythroleukemia cells as summarized in Fig. 8. Jervine did not induce apoptosis but induced COX-2 overexpression. Furthermore, NF-κB was activated and its inhibition led to a reduction of COX-2 overexpression and to an induction of apoptosis. We could conclude then, that the pro-apoptotic potential of jervine was restrained by activation of

Conflict of interest statement

The authors declare no conflict of interest.

Acknowledgments

The authors are grateful to Claire Carion for help in performing mitochondrial membrane potential assays. This research was supported by grants from the French Ministry of Education and Research and from the Conseil Régional du Limousin.

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Research ArticleCyclopamine and jervine induce COX-2 overexpression in human erythroleukemia cells but only cyclopamine has a pro-apoptotic effect

Abstract

Highlights

Introduction

Section snippets

Materials

Cyclopamine but not jervine inhibited the HEL and TF1a cell growth

Discussion

Conclusions

Conflict of interest statement

Acknowledgments

Dev. Biol.

Eur. J. Cancer

Leuk. Res.

Exp. Cell Res.

Biochimie

Biochimie

Exp. Cell Res.

Arch. Med. Res.

Bioorg. Med. Chem.

Cancer Cell

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Cell. Signal.

J. Biol. Chem.

The intersection of genetic and chemical genomic screens identifies GSK-3alpha as a target in human acute myeloid leukemia

J. Clin. Invest.

Morphologic characteristics of erythroleukemia (acute myeloid leukemia; FAB-M6): a CALGB study

Am. J. Hematol.

Acute erythroleukemia: diagnosis and management

Expert Rev. Hematol.

Investigating the relationship between cell cycle stage and diosgenin-induced megakaryocytic differentiation of HEL cells using sedimentation field-flow fractionation

Anal. Bioanal. Chem.

Role of MAPKs and NF-kappaB in diosgenin-induced megakaryocytic differentiation and subsequent apoptosis in HEL cells

Int. J. Oncol.

Cyclooxygenase in biology and disease

FASEB J.

Cyclooxygenases: structural, cellular, and molecular biology

Annu. Rev. Biochem.

Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing

Proc. Nat. Acad. Sci. U.S.A.

Many actions of cyclooxygenase-2 in cellular dynamics and in cancer

J. Cell. Physiol.

Research Article
Cyclopamine and jervine induce COX-2 overexpression in human erythroleukemia cells but only cyclopamine has a pro-apoptotic effect