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Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor ?-KLF5 Pathway.

ABSTRACT: Estrogens are effective in the treatment of prostate cancer; however, the effects of estrogens on prostate cancer are enigmatic. In this study, we demonstrated that estrogen (17?-estradiol [E2]) has biphasic effects on prostate tumor growth. A lower dose of E2 increased tumor growth in mouse xenograft models using DU145 and PC-3 human prostate cancer cells, whereas a higher dose significantly decreased tumor growth. We found that anchorage-independent apoptosis in these cells was inhibited by E2 treatment. Similarly, in vivo angiogenesis was suppressed by E2. Interestingly, these effects of E2 were abolished by knockdown of either estrogen receptor ? (ER?) or Krüppel-like zinc finger transcription factor 5 (KLF5). ?n addition, E2 suppressed KLF5-mediated transcription through ER?, which inhibits proapoptotic FOXO1 and proangiogenic PDGFA expression. Furthermore, we revealed that a nonagonistic ER ligand GS-1405 inhibited FOXO1 and PDGFA expression through the ER?-KLF5 pathway and regulated prostate tumor growth without ER? transactivation. Therefore, these results suggest that E2 biphasically modulates prostate tumor formation by regulating KLF5-dependent transcription through ER? and provide a new strategy for designing ER modulators, which will be able to regulate prostate cancer progression with minimal adverse effects due to ER transactivation.

SUBMITTER: Nakajima Y

PROVIDER: S-EPMC4702593 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway.

Nakajima Yuka Y Osakabe Asami A Waku Tsuyoshi T Suzuki Takashi T Akaogi Kensuke K Fujimura Tetsuya T Homma Yukio Y Inoue Satoshi S Yanagisawa Junn J

Molecular and cellular biology 20151019 1

Estrogens are effective in the treatment of prostate cancer; however, the effects of estrogens on prostate cancer are enigmatic. In this study, we demonstrated that estrogen (17β-estradiol [E2]) has biphasic effects on prostate tumor growth. A lower dose of E2 increased tumor growth in mouse xenograft models using DU145 and PC-3 human prostate cancer cells, whereas a higher dose significantly decreased tumor growth. We found that anchorage-independent apoptosis in these cells was inhibited by E2 ...[more]

PMID: 26483416

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Project description:BackgroundCastration-resistant prostate cancer often metastasizes to the bone, and such bone metastases eventually become resistant to available therapies, leading to the death of patients. Enriched in the bone, TGF-β plays a pivotal role in bone metastasis development. However, directly targeting TGF-β or its receptors has been challenging for the treatment of bone metastasis. We previously found that TGF-β induces and then depends on the acetylation of transcription factor KLF5 at K369 to regulate multiple biological processes, including the induction of EMT, cellular invasiveness, and bone metastasis. Acetylated KLF5 (Ac-KLF5) and its downstream effectors are thus potential therapeutic targets for treating TGF-β-induced bone metastasis in prostate cancer.MethodsA spheroid invasion assay was applied to prostate cancer cells expressing KLF5K369Q, which mimics Ac-KLF5, to screen 1987 FDA-approved drugs for invasion suppression. Luciferase- and KLF5K369Q-expressing cells were injected into nude mice via the tail artery to model bone metastasis. Bioluminescence imaging, micro-CT), and histological analyses were applied to monitor and evaluate bone metastases. RNA-sequencing, bioinformatic, and biochemical analyses were used to understand nitazoxanide (NTZ)-regulated genes, signaling pathways, and the underlying mechanisms. The binding of NTZ to KLF5 proteins was evaluated using fluorescence titration, high-performance liquid chromatography (HPLC), and circular dichroism (CD) analysis.ResultsNTZ, an anthelmintic agent, was identified as a potent invasion inhibitor in the screening and validation assays. In KLF5K369Q-induced bone metastasis, NTZ exerted a potent inhibitory effect in preventive and therapeutic modes. NTZ also inhibited osteoclast differentiation, a cellular process responsible for bone metastasis induced by KLF5K369Q. NTZ attenuated the function of KLF5K369Q in 127 genes' upregulation and 114 genes' downregulation. Some genes' expression changes were significantly associated with worse overall survival in patients with prostate cancer. One such change was the upregulation of MYBL2, which functionally promotes bone metastasis in prostate cancer. Additional analyses demonstrated that NTZ bound to the KLF5 protein, KLF5K369Q bound to the promoter of MYBL2 to activate its transcription, and NTZ attenuated the binding of KLF5K369Q to the MYBL2 promoter.ConclusionsNTZ is a potential therapeutic agent for bone metastasis induced by the TGF-β/Ac-KLF5 signaling axis in prostate cancer and likely other cancers.

Dataset Information

Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor ?-KLF5 Pathway.

Publications

Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway.

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