title: Arachidonic acid pathway members PLA2G7, HPGD, EPHX2, and CYP4F8 identified as putative novel therapeutic targets in prostate cancer.
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.
authors.affiliation: Turku Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Paula
authors.initials: P
authors.lastname: Vainio
authors.forename: Santosh
authors.initials: S
authors.lastname: Gupta
authors.forename: Kirsi
authors.initials: K
authors.lastname: Ketola
authors.forename: Tuomas
authors.initials: T
authors.lastname: Mirtti
authors.forename: John-Patrick
authors.initials: JP
authors.lastname: Mpindi
authors.forename: Pekka
authors.initials: P
authors.lastname: Kohonen
authors.forename: Vidal
authors.initials: V
authors.lastname: Fey
authors.forename: Merja
authors.initials: M
authors.lastname: Perälä
authors.forename: Frank
authors.initials: F
authors.lastname: Smit
authors.forename: Gerald
authors.initials: G
authors.lastname: Verhaegh
authors.forename: Jack
authors.initials: J
authors.lastname: Schalken
authors.forename: Kalle A
authors.initials: KA
authors.lastname: Alanen
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.forename: Kristiina
authors.initials: K
authors.lastname: Iljin
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000368:Aged; D000369:Aged, 80 and over; D016718:Arachidonic Acid / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005485:Flutamide / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*
chemical_list: D009363:Neoplasm Proteins; D064801:Phospholipase A2 Inhibitors; D012333:RNA, Messenger; D011944:Receptors, Androgen; D016718:Arachidonic Acid; D005485:Flutamide; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D001189:Aryl Hydrocarbon Hydroxylases; C120451:CYP4F8 protein, human; D054467:Phospholipases A2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C526684:PLA2G7 protein, human; D004851:Epoxide Hydrolases; C506428:EPHX2 protein, human