Mevalonate pathway antagonist suppresses formation of serous tubal intraepithelial carcinoma and ovarian carcinoma in mouse models

Yusuke Kobayashi, Hiroyasu Kashima, Ren Chin Wu, Jin Gyoung Jung, Jen Chun Kuan, Jinghua Gu, Jianhua Xuan, Lori Sokoll, Kala Visvanathan, Ie Ming Shih, Tian Li Wang

Research output: Contribution to journalArticle

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Abstract

Purpose: Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Because TP53 mutations occur in almost all ovarian high-grade serous carcinoma (HGSC), we determined whether statins suppressed tumor growth in animal models of ovarian cancer. Experimental Design: Two ovarian cancer mouse models were used. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously developed serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the antitumor effects of lovastatin were also investigated. Results: Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced antiproliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells. Conclusions: The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease.

Original languageEnglish
Pages (from-to)4652-4662
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number20
DOIs
Publication statusPublished - 2015 Oct 15

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Mevalonic Acid
Carcinoma in Situ
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Lovastatin
Ovarian Neoplasms
Carcinoma
Neoplasms
Heterografts
Growth
Drug Repositioning
Prenylation
Polyomavirus Transforming Antigens
Mutation
Oviducts
Gene Expression Profiling
Glycolysis
Hypercholesterolemia
DNA Replication
Glycoproteins
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Mevalonate pathway antagonist suppresses formation of serous tubal intraepithelial carcinoma and ovarian carcinoma in mouse models. / Kobayashi, Yusuke; Kashima, Hiroyasu; Wu, Ren Chin; Jung, Jin Gyoung; Kuan, Jen Chun; Gu, Jinghua; Xuan, Jianhua; Sokoll, Lori; Visvanathan, Kala; Shih, Ie Ming; Wang, Tian Li.

In: Clinical Cancer Research, Vol. 21, No. 20, 15.10.2015, p. 4652-4662.

Research output: Contribution to journalArticle

Kobayashi, Y, Kashima, H, Wu, RC, Jung, JG, Kuan, JC, Gu, J, Xuan, J, Sokoll, L, Visvanathan, K, Shih, IM & Wang, TL 2015, 'Mevalonate pathway antagonist suppresses formation of serous tubal intraepithelial carcinoma and ovarian carcinoma in mouse models', Clinical Cancer Research, vol. 21, no. 20, pp. 4652-4662. https://doi.org/10.1158/1078-0432.CCR-14-3368
Kobayashi, Yusuke ; Kashima, Hiroyasu ; Wu, Ren Chin ; Jung, Jin Gyoung ; Kuan, Jen Chun ; Gu, Jinghua ; Xuan, Jianhua ; Sokoll, Lori ; Visvanathan, Kala ; Shih, Ie Ming ; Wang, Tian Li. / Mevalonate pathway antagonist suppresses formation of serous tubal intraepithelial carcinoma and ovarian carcinoma in mouse models. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 20. pp. 4652-4662.
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T1 - Mevalonate pathway antagonist suppresses formation of serous tubal intraepithelial carcinoma and ovarian carcinoma in mouse models

AU - Kobayashi, Yusuke

AU - Kashima, Hiroyasu

AU - Wu, Ren Chin

AU - Jung, Jin Gyoung

AU - Kuan, Jen Chun

AU - Gu, Jinghua

AU - Xuan, Jianhua

AU - Sokoll, Lori

AU - Visvanathan, Kala

AU - Shih, Ie Ming

AU - Wang, Tian Li

PY - 2015/10/15

Y1 - 2015/10/15

N2 - Purpose: Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Because TP53 mutations occur in almost all ovarian high-grade serous carcinoma (HGSC), we determined whether statins suppressed tumor growth in animal models of ovarian cancer. Experimental Design: Two ovarian cancer mouse models were used. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously developed serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the antitumor effects of lovastatin were also investigated. Results: Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced antiproliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells. Conclusions: The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease.

AB - Purpose: Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Because TP53 mutations occur in almost all ovarian high-grade serous carcinoma (HGSC), we determined whether statins suppressed tumor growth in animal models of ovarian cancer. Experimental Design: Two ovarian cancer mouse models were used. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously developed serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the antitumor effects of lovastatin were also investigated. Results: Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced antiproliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells. Conclusions: The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease.

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