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

Paula Vainio, Santosh Gupta, Kirsi Ketola, T. Mirtti, John Mpindi, Pekka Kohonen, Vidal Fey, Merja Perälä, F. Smit, G. Verhaegh, J. Schalken, K.A. Alanen, Olli Kallioniemi, Kristiina Iljin (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

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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.
Original languageEnglish
Pages (from-to)525-536
Number of pages12
JournalAmerican Journal of Pathology
Volume178
Issue number2
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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Arachidonic Acid
Prostatic Neoplasms
Androgen Receptors
Therapeutics
Oxidative Stress
Flutamide
Androgen Antagonists
Essential Genes
RNA Interference
Computational Biology
Oncogenes
Androgens
Genes
Prostaglandins
Prostate
Cell Survival
Carcinogenesis
Biomarkers
Messenger RNA
Enzymes

Cite this

Vainio, Paula ; Gupta, Santosh ; Ketola, Kirsi ; Mirtti, T. ; Mpindi, John ; Kohonen, Pekka ; Fey, Vidal ; Perälä, Merja ; Smit, F. ; Verhaegh, G. ; Schalken, J. ; Alanen, K.A. ; Kallioniemi, Olli ; Iljin, Kristiina. / Arachidonic acid pathway members PLA2G7, HPGD, EPHX2, and CYP4F8 identified as putative novel therapeutic targets in prostate cancer. In: American Journal of Pathology. 2011 ; Vol. 178, No. 2. pp. 525-536.
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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.",
author = "Paula Vainio and Santosh Gupta and Kirsi Ketola and T. Mirtti and John Mpindi and Pekka Kohonen and Vidal Fey and Merja Per{\"a}l{\"a} and F. Smit and G. Verhaegh and J. Schalken and K.A. Alanen and Olli Kallioniemi and Kristiina Iljin",
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Vainio, P, Gupta, S, Ketola, K, Mirtti, T, Mpindi, J, Kohonen, P, Fey, V, Perälä, M, Smit, F, Verhaegh, G, Schalken, J, Alanen, KA, Kallioniemi, O & Iljin, K 2011, 'Arachidonic acid pathway members PLA2G7, HPGD, EPHX2, and CYP4F8 identified as putative novel therapeutic targets in prostate cancer', American Journal of Pathology, vol. 178, no. 2, pp. 525-536. https://doi.org/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. / Vainio, Paula; Gupta, Santosh; Ketola, Kirsi; Mirtti, T.; Mpindi, John; Kohonen, Pekka; Fey, Vidal; Perälä, Merja; Smit, F.; Verhaegh, G.; Schalken, J.; Alanen, K.A.; Kallioniemi, Olli; Iljin, Kristiina (Corresponding Author).

In: American Journal of Pathology, Vol. 178, No. 2, 2011, p. 525-536.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Arachidonic acid pathway members PLA2G7, HPGD, EPHX2, and CYP4F8 identified as putative novel therapeutic targets in prostate cancer

AU - Vainio, Paula

AU - Gupta, Santosh

AU - Ketola, Kirsi

AU - Mirtti, T.

AU - Mpindi, John

AU - Kohonen, Pekka

AU - Fey, Vidal

AU - Perälä, Merja

AU - Smit, F.

AU - Verhaegh, G.

AU - Schalken, J.

AU - Alanen, K.A.

AU - Kallioniemi, Olli

AU - Iljin, Kristiina

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

U2 - 10.1016/j.ajpath.2010.10.002

DO - 10.1016/j.ajpath.2010.10.002

M3 - Article

VL - 178

SP - 525

EP - 536

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 2

ER -