Cytochrome P450 2J2 is highly expressed in hematologic malignant diseases and promotes tumor cell growth

Chen Chen, Xin Wei, Xiaoquan Rao, Jun Wu, Shenglan Yang, Fuqiong Chen, Ding Ma, Jianfeng Zhou, Ryan T. Dackor, Darryl C. Zeldin, Dao Wen Wang

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Cytochrome P450 2J2 (CYP2J2) epoxygenase converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs) that exert multiple biological effects in the cardiovascular system and in various human solid cancers. However, it is unknown whether this enzyme is expressed or plays any role in malignant hematological diseases. In this study, we found strong and highly selective CYP2J2 expression in five human-derived malignant hematological cell lines and in leukemia cells from peripheral blood and bone marrow in 36 of 42 patients (86%) with malignant hematologic diseases. Furthermore, increased levels of EETs were detected in urine and blood samples from these patients. Addition of exogenous EET or CYP2J2 overexpression in cultured human-derived malignant hematologic cell lines markedly accelerated proliferation and attenuated apoptosis. Addition of the selective CYP2J2 inhibitor compound 26 (C26; 1-[4-(vinyl) phenyl]-4-[4-(diphenyl-hydroxymethyl)-piperidinyl]-butanone hydrochloride) inhibited cell proliferation and increased apoptosis, an effect that was significantly reversed by EET. CYP2J2 overexpression and exogenous EET activated AMP-activated protein kinase, c-Jun NH2-terminal kinase, and phosphatidylinositol 3-kinase/Akt signaling pathways, and increased epidermal growth factor receptor phosphorylation levels. CYP2J2 overexpression also enhanced malignant xenograft growth, which was efficiently inhibited by oral administration of C26 in Tie2-CYP2J2 transgenic mice and in severe combined immunodeficiency (SCID) xenograft mice. Together, these results suggest that CYP2J2 plays a key role in the pathogenesis of human hematologic malignant diseases. Selective inhibition of CYP2J2 may be a promising therapeutic strategy for these conditions.

Original languageEnglish (US)
Pages (from-to)344-355
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume336
Issue number2
DOIs
StatePublished - Feb 1 2011
Externally publishedYes

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Hematologic Diseases
Cytochrome P-450 Enzyme System
Growth
Neoplasms
Heterografts
Phosphatidylinositol 3-Kinase
Apoptosis
Butanones
Cell Line
Severe Combined Immunodeficiency
AMP-Activated Protein Kinases
JNK Mitogen-Activated Protein Kinases
Cardiovascular System
Epidermal Growth Factor Receptor
Transgenic Mice
Oral Administration
Blood Cells
Leukemia
Bone Marrow
Phosphorylation

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Cytochrome P450 2J2 is highly expressed in hematologic malignant diseases and promotes tumor cell growth. / Chen, Chen; Wei, Xin; Rao, Xiaoquan; Wu, Jun; Yang, Shenglan; Chen, Fuqiong; Ma, Ding; Zhou, Jianfeng; Dackor, Ryan T.; Zeldin, Darryl C.; Wang, Dao Wen.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 336, No. 2, 01.02.2011, p. 344-355.

Research output: Contribution to journalArticle

Chen, Chen ; Wei, Xin ; Rao, Xiaoquan ; Wu, Jun ; Yang, Shenglan ; Chen, Fuqiong ; Ma, Ding ; Zhou, Jianfeng ; Dackor, Ryan T. ; Zeldin, Darryl C. ; Wang, Dao Wen. / Cytochrome P450 2J2 is highly expressed in hematologic malignant diseases and promotes tumor cell growth. In: Journal of Pharmacology and Experimental Therapeutics. 2011 ; Vol. 336, No. 2. pp. 344-355.
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abstract = "Cytochrome P450 2J2 (CYP2J2) epoxygenase converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs) that exert multiple biological effects in the cardiovascular system and in various human solid cancers. However, it is unknown whether this enzyme is expressed or plays any role in malignant hematological diseases. In this study, we found strong and highly selective CYP2J2 expression in five human-derived malignant hematological cell lines and in leukemia cells from peripheral blood and bone marrow in 36 of 42 patients (86{\%}) with malignant hematologic diseases. Furthermore, increased levels of EETs were detected in urine and blood samples from these patients. Addition of exogenous EET or CYP2J2 overexpression in cultured human-derived malignant hematologic cell lines markedly accelerated proliferation and attenuated apoptosis. Addition of the selective CYP2J2 inhibitor compound 26 (C26; 1-[4-(vinyl) phenyl]-4-[4-(diphenyl-hydroxymethyl)-piperidinyl]-butanone hydrochloride) inhibited cell proliferation and increased apoptosis, an effect that was significantly reversed by EET. CYP2J2 overexpression and exogenous EET activated AMP-activated protein kinase, c-Jun NH2-terminal kinase, and phosphatidylinositol 3-kinase/Akt signaling pathways, and increased epidermal growth factor receptor phosphorylation levels. CYP2J2 overexpression also enhanced malignant xenograft growth, which was efficiently inhibited by oral administration of C26 in Tie2-CYP2J2 transgenic mice and in severe combined immunodeficiency (SCID) xenograft mice. Together, these results suggest that CYP2J2 plays a key role in the pathogenesis of human hematologic malignant diseases. Selective inhibition of CYP2J2 may be a promising therapeutic strategy for these conditions.",
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AU - Wei, Xin

AU - Rao, Xiaoquan

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AU - Chen, Fuqiong

AU - Ma, Ding

AU - Zhou, Jianfeng

AU - Dackor, Ryan T.

AU - Zeldin, Darryl C.

AU - Wang, Dao Wen

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