title: Tumor-specifically hypoxia-induced therapy of SPRY1/2 displayed differential therapeutic efficacy for melanoma.
abstract: Activation of receptor tyrosine kinase (RTK) signalling pathways is frequently correlated to cancer cell proliferation, angiogenesis and cell survival. Sprouty (SPRY) proteins function as a physiological endogenous inhibitor of RTK signalling pathways, have been shown to be deregulated in most cancer cells. Here, we demonstrated that over-expression of SPRY1 and SPRY2 inhibited B16F10 cell proliferation through G1 phase arrest in vitro, and SPRY2 showed more potent inhibitory effects than SPRY1. In order to tumor-specific delivery of SPRY1/2 in vivo, two strains of attenuated Salmonella typhimurium VNP20009 (VNP-PQE-SPRY1 and VNP-PQE-SPRY2) were constructed to specifically express SPRY1 or SPRY2 under the control of a hypoxia-induced nirB promoter. The efficiency and specificity of the recombinant strains were validated in both bacteria and animal tumor models. SPRY1 and SPRY2 gene could be specifically driven by the nirB promoter under hypoxia, but not normoxia conditions. In addition, the tumor-targeting ability of VNP-PQE-SPRY1 or VNP-PQE-SPRY2 was similar with VNP. VNP-PQE-SPRY2 significantly suppressed melanoma growth in vivo, suggesting that SPRY2 is a more efficient agent for melanoma therapy. Moreover, the antitumor effect of VNP-SPRY2 is mainly mediated through the inhibition of ERK1/2 phosphorylation, which leads to the inhibition of proliferation in melanoma. Taken together, our results indicated that SPRY2 displayed more potent melanoma suppression than SPRY1 both in vitro and in vivo, and the hypoxia-induced tumor-specific gene therapy of SPRY2 delivered by VNP20009 is a promising strategy for melanoma therapy.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University Nanjing, Jiangsu 210093, China ; State Key Laboratory of Natural Medicines, China Pharmaceutical University Nanjing, Jiangsu 210009, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University Nanjing, Jiangsu 210093, China ; The Stake Key Laboratory of Natural and Biomimetic Drugs, Peking University Beijing 100191, China.
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University Nanjing, Jiangsu 210093, China.
authors.forename: Wenmin
authors.initials: W
authors.lastname: Cao
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University Nanjing, Jiangsu 210093, China ; Nanjing Industrial Innovation Center for Pharmaceutical Biotechnology Nanjing, Jiangsu 210019, China ; Changzhou High-Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories Inc. Changzhou, 213164, Jiangsu, China.
authors.forename: Zi-Chun
authors.initials: ZC
authors.lastname: Hua
keywords: SPRY1; SPRY2; attenuated Salmonella typhimurium VNP20009; melanoma gene therapy