Journal
THERANOSTICS
Volume 11, Issue 13, Pages 6526-6541Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.53886
Keywords
SIRT6; castration-resistant prostate cancer; Notch pathway; therapy; engineered exosomes
Categories
Funding
- National Natural Science Foundation of China [81773115, 31801187]
- Science and Technology Commission of Shanghai Municipality [19ZR143100]
- Shanghai Jiao Tong University [YG2017MS52]
- Laboratory for Synthetic Chemistry and Chemical Biology under the Health@InnoHK Program
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SIRT6 expression is positively correlated with prostate cancer progression, and its loss significantly suppresses proliferation and metastasis of prostate cancer cells. Delivery of siRNA through engineered exosomes can effectively inhibit SIRT6 and consequently inhibit tumor growth and metastasis.
The treatment for metastatic castration-resistant prostate cancer patients remains a great challenge in the clinic and continuously demands discoveries of new targets and therapies. Here, we assess the function and therapeutic value of SIRT6 in metastatic castration-resistant prostate cancer. Methods: The expression of SIRT6 was examined in prostate cancer tissue microarray by immunohistochemistry staining. The functions of SIRT6 and underlying mechanisms were elucidated by in vitro and in vivo experiments. We also developed an efficient method to silence SIRT6 by aptamer-modified exosomes carrying small interfering RNA and tested the therapeutic effect in the xenograft mice models. Results: SIRT6 expression is positively correlated with prostate cancer progression. Loss of SIRT6 significantly suppressed proliferation and metastasis of prostate cancer cell lines both in vitro and in vivo. SIRT6-driven prostate cancer displays activation of multiple cancer-related signaling pathways, especially the Notch pathway. Silencing SIRT6 by siRNA delivered through engineered exosomes inhibited tumor growth and metastasis. Conclusions: SIRT6 is identified as a driver and therapeutic target for metastatic prostate cancer in our findings, and inhibition of SIRT6 by engineered exosomes can serve as a promising therapeutic tool for clinical application.
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