Arachidonic acid pathway members PLA2G7, HPGD, EPHX2, and CYP4F8 identified as putative novel therapeutic targets in prostate cancer

Paula Vainio; Santosh Gupta; Kirsi Ketola; Tuomas Mirtti; John-Patrick Mpindi; Pekka Kohonen; Vidal Fey; Merja Perälä; Frank Smit; Gerald Verhaegh; Jack Schalken; Kalle A Alanen; Olli Kallioniemi; Kristiina Iljin

doi:10.1016/j.ajpath.2010.10.002

Arachidonic acid pathway members PLA2G7, HPGD, EPHX2, and CYP4F8 identified as putative novel therapeutic targets in prostate cancer

Am J Pathol. 2011 Feb;178(2):525-36. doi: 10.1016/j.ajpath.2010.10.002.

Authors

Paula Vainio¹, Santosh Gupta, Kirsi Ketola, Tuomas Mirtti, John-Patrick Mpindi, Pekka Kohonen, Vidal Fey, Merja Perälä, Frank Smit, Gerald Verhaegh, Jack Schalken, Kalle A Alanen, Olli Kallioniemi, Kristiina Iljin

Affiliation

¹ Turku Centre for Biotechnology, University of Turku, Turku, Finland.

Abstract

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 PLA2G7, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-Alkyl-2-acetylglycerophosphocholine Esterase
Aged
Aged, 80 and over
Arachidonic Acid / metabolism*
Aryl Hydrocarbon Hydroxylases / genetics
Aryl Hydrocarbon Hydroxylases / metabolism
Cell Proliferation / drug effects
Epoxide Hydrolases / antagonists & inhibitors
Epoxide Hydrolases / genetics
Epoxide Hydrolases / metabolism
Flutamide / pharmacology
Flutamide / therapeutic use
Gene Expression Regulation, Neoplastic / drug effects
Gene Silencing / drug effects
Humans
Hydroxyprostaglandin Dehydrogenases / genetics
Hydroxyprostaglandin Dehydrogenases / metabolism
Male
Middle Aged
Molecular Targeted Therapy*
Neoplasm Proteins / genetics*
Neoplasm Proteins / metabolism*
Oxidative Stress / drug effects
Oxidative Stress / genetics
Phospholipase A2 Inhibitors
Phospholipases A2 / genetics
Phospholipases A2 / metabolism
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / enzymology
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / pathology
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, Androgen / genetics
Receptors, Androgen / metabolism
Reproducibility of Results
Signal Transduction / drug effects
Signal Transduction / genetics*

Substances

Neoplasm Proteins
Phospholipase A2 Inhibitors
RNA, Messenger
Receptors, Androgen
Arachidonic Acid
Flutamide
Hydroxyprostaglandin Dehydrogenases
15-hydroxyprostaglandin dehydrogenase
Aryl Hydrocarbon Hydroxylases
CYP4F8 protein, human
Phospholipases A2
1-Alkyl-2-acetylglycerophosphocholine Esterase
PLA2G7 protein, human
Epoxide Hydrolases
EPHX2 protein, human