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Metformin reverses prostate cancer resistance to enzalutamide by targeting TGF-?1/STAT3 axis-regulated EMT.


ABSTRACT: Although the newly developed second-generation anti-androgen drug enzalutamide can repress prostate cancer progression significantly, it only extends the survival of prostate cancer patients by 4-6 months mainly due to the occurrence of enzalutamide resistance. Most of the previous studies on AR antagonist resistance have been focused on AR signaling. Therefore, the non-AR pathways on enzalutamide resistance remain largely unknown. By using C4-2, CWR22Rv1 and LNCaP cell lines, as well as mice bearing CWR22Rv1 xenografts treated with either enzalutamide or metformin alone or in combination, we demonstrated that metformin is capable of reversing enzalutamide resistance and restores sensitivity of CWR22Rv1 xenografts to enzalutamide. We showed that metformin alleviated resistance to enzalutamide by inhibiting EMT. Furthermore, based on the effect of metformin on the activation of STAT3 and expression of TGF-?1, we propose that metformin exerts its effects by targeting the TGF-?1/STAT3 axis. These findings suggest that combination of metformin with enzalutamide could be a more efficacious therapeutic strategy for the treatment of castration-resistant prostate cancer.

SUBMITTER: Liu Q 

PROVIDER: S-EPMC5596596 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Metformin reverses prostate cancer resistance to enzalutamide by targeting TGF-β1/STAT3 axis-regulated EMT.

Liu Qiuli Q   Tong Dali D   Liu Gaolei G   Xu Jing J   Do Khang K   Geary Kyla K   Zhang Dianzheng D   Zhang Jun J   Zhang Yao Y   Li Yaoming Y   Bi Gang G   Lan Weihua W   Jiang Jun J  

Cell death & disease 20170824 8


Although the newly developed second-generation anti-androgen drug enzalutamide can repress prostate cancer progression significantly, it only extends the survival of prostate cancer patients by 4-6 months mainly due to the occurrence of enzalutamide resistance. Most of the previous studies on AR antagonist resistance have been focused on AR signaling. Therefore, the non-AR pathways on enzalutamide resistance remain largely unknown. By using C4-2, CWR22Rv1 and LNCaP cell lines, as well as mice be  ...[more]

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