Arachidonic Acid Pathway Members PLA2G7, HPGD, EPHX2, and CYP4F8 Identified as Putative Novel Therapeutic Targets in Prostate Cancer

被引：93

作者：

Vainio, Paula ^{[2
]}

Gupta, Santosh ^{[2
]}

Ketola, Kirsi ^{[2
]}

Mirtti, Tuomas ^{[3
]}

Mpindi, John-Patrick ^{[4
]}

Kohonen, Pekka ^{[2
]}

Fey, Vidal ^{[1
]}

Perala, Merja ^{[1
]}

Smit, Frank ^{[5
]}

Verhaegh, Gerald ^{[5
]}

Schalken, Jack ^{[5
]}

Alanen, Kalle A. ^{[3
]}

Kallioniemi, Olli ^{[1
,2
,4
]}

Iljin, Kristiina ^{[1
,2
]}

机构：

[1] VTT Tech Res Ctr Finland, Turku 20521, Finland

[2] Univ Turku, Turku Ctr Biotechnol, Turku, Finland

[3] Turku Univ Hosp, Dept Pathol, FIN-20520 Turku, Finland

[4] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

[5] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 ED Nijmegen, Netherlands

来源：

AMERICAN JOURNAL OF PATHOLOGY | 2011年 / 178卷 / 02期

基金：

芬兰科学院;

关键词：

SOLUBLE EPOXIDE HYDROLASE; 15-HYDROXYPROSTAGLANDIN DEHYDROGENASE EXPRESSION; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ENDOTHELIAL GROWTH-FACTOR; PHOSPHOLIPASE A(2); TUMOR-SUPPRESSOR; 15-LIPOXYGENASE-2; 15-LOX2; SUBCELLULAR-LOCALIZATION; ONCOGENIC ACTION; BREAST-CANCER;

D O I：

10.1016/j.ajpath.2010.10.002

中图分类号：

R36 [病理学];

学科分类号：

100104 ;

摘要：

The arachidonic acid and prostaglandin pathway has been implicated in prostate carcinogenesis, but comprehensive studies of the individual members in this key pathway are lacking. Here, we first conducted a systematic bioinformatic study of the expression of 36 arachidonic acid pathway genes across 9783 human tissue samples. The results showed that the PL42G7, HPGD, EPHX2, and CYP4F8 genes are highly expressed in prostate cancer. Functional studies using RNA interference in prostate cancer cells indicated that all four genes are also essential for cell growth and survival. Clinical validation confirmed high PLA2G7 expression, especially in ERG oncogene-positive prostate cancers, and its silencing sensitized ERG-positive prostate cancer cells to oxidative stress. HPGD was highly expressed in androgen receptor (AR)-overexpressing advanced tumors, as well as in metastatic prostate cancers. EPHX2 mRNA correlated with AR in primary prostate cancers, and its inhibition in vitro reduced AR signaling and potentiated the effect of antiandrogen flutamide in cultured prostate cancer cells. In summary, we identified four novel putative therapeutic targets with biomarker potential for different subtypes of prostate cancer. In addition, our results indicate that inhibition of these enzymes may be particularly powerful when combined with other treatments, such as androgen deprivation or induction of oxidative stress. (Am J Pathol 2011, 17&-.525-53 DOI: 10.1016/j.ajpath.2010.10.002)

引用

页码：525 / 536

页数：12

共 54 条

[1] Antitumor Activity with CYP17 Blockade Indicates That Castration-Resistant Prostate Cancer Frequently Remains Hormone Driven [J].