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Overexpression of SOCS3 mediated by adenovirus vector in mouse and human castration-resistant prostate cancer cells increases the sensitivity to NK cells in vitro and in vivo

Abstract

Prostate cancer is one of the most common cancers in men. The overactivation of IL-6/JAK/STAT3 signaling and silencing of SOCS3 are frequently observed in prostate cancer. In the present study we undertook to develop Ad-SOCS3 gene therapy for the treatment of prostate cancer and also investigated whether Ad-SOCS3 increased sensitivity to NK cells. We demonstrated that Ad-SOCS3 could significantly inhibit growth of castration-resistant prostate cancer (CRPC) cell lines expressing pSTAT3, DU-145 (at 10, 20, and 40 MOI), and TRAMP-C2 (at 40 MOI), but not the PC-3 CRPC cell line with the STAT3 gene deleted. Ad-SOCS3 (40 MOI) could suppress IL-6 production in DU-145 cells and PD-L1 expression induced by IFN-γ in TRAMP-C2 cells, and increased the NK cell sensitivity of both TRAMP-C2 and DU-145 cells. In the DU-145 mouse xenograft tumor model, intratumoral injections (twice/week for 3 weeks) of 1 × 108 pfu of Ad-SOCS3 significantly inhibited tumor growth and combining the Ad-SOCS3 treatment with intratumoral injections (once/week for 2 weeks) of 1 × 107 human NK cells showed the highest tumor growth inhibitory effect. These results suggested that a combination of Ad-SOCS3 gene therapy and NK cell immunotherapy could be a powerful treatment option for advanced CRPC overexpressing pSTAT3.

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Acknowledgements

This research was supported by Japan Agency for Medical Research and Development (AMED) under grant number JP16ck0106106. The authors wish to acknowledge Mr. Gary Mawyer for his great support for proofreading.

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Correspondence to Toshiro Shirakawa.

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Yoneda, T., Kunimura, N., Kitagawa, K. et al. Overexpression of SOCS3 mediated by adenovirus vector in mouse and human castration-resistant prostate cancer cells increases the sensitivity to NK cells in vitro and in vivo. Cancer Gene Ther 26, 388–399 (2019). https://doi.org/10.1038/s41417-018-0075-5

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