TY - JOUR
T1 - Robust Anticancer Efficacy of a Biologically Synthesized Tumor Acidity-Responsive and Autophagy-Inducing Functional Beclin 1
AU - Ding, Guo Bin
AU - Sun, Junqing
AU - Wu, Gengfeng
AU - Li, Binchun
AU - Yang, Peng
AU - Li, Zhuoyu
AU - Nie, Guangjun
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (No. 31500771), Scientific and Technological Innovation Program of Higher Education Institutions in Shanxi Province (STIP, No. 2015116), and 1331 Project Key Innovation Team of Shanxi Province (Prof. Zhuoyu Li). We are grateful to Dr. Jun Du from Institute of Biotechnology of Shanxi University for his helpful discussion in CFDA-SE staining assay.
Funding Information:
This work was supported by the National Natural Science Foundation of China (No. 31500771), Scientific and Technological Innovation Program of Higher Education Institutions in Shanxi Province (STIP, No. 2015116), and “1331 Project” Key Innovation Team of Shanxi Province (Prof. Zhuoyu Li). We are grateful to Dr. Jun Du from Institute of Biotechnology of Shanxi University for his helpful discussion in CFDA-SE staining assay.
Publisher Copyright:
© 2018 American Chemical Society.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2018/2/14
Y1 - 2018/2/14
N2 - As a potent autophagy inducer, Beclin 1 is essential for the initiation of autophagic cell death, and triggering extensive autophagy by targeted delivery of Beclin 1 to tumors has enormous potential to inhibit tumor growth. Yet, the therapeutic application of Beclin 1 is hampered by its inability to internalize into cells and nonselective biodistribution in vivo. To tackle this challenge, we employed a novel Beclin 1 delivery manner by constructing a functional protein (Trx-pHLIP-Beclin 1, TpB) composed of a thioredoxin (Trx) tag, a pH low insertion peptide (pHLIP), and an evolutionarily conserved motif of Beclin 1. This protein could effectively transport Beclin 1 to breast and ovarian cancer cell lines under weakly acidic conditions (pH 6.5), markedly inhibit tumor cell growth and proliferation, and induce obvious autophagy. Furthermore, the in vivo antitumor efficacy of the functional Beclin 1 against an SKOV3 xenograft tumor mouse model was tested via intravenous injection. TpB preferentially accumulated in tumors and exhibited a significantly higher tumor growth inhibition than the nontargeted Beclin 1 control, whereas no overt side effects were observed. Taken together, this study sheds light on the potential application of TpB as a highly efficient yet safe antitumor agent for cancer treatment.
AB - As a potent autophagy inducer, Beclin 1 is essential for the initiation of autophagic cell death, and triggering extensive autophagy by targeted delivery of Beclin 1 to tumors has enormous potential to inhibit tumor growth. Yet, the therapeutic application of Beclin 1 is hampered by its inability to internalize into cells and nonselective biodistribution in vivo. To tackle this challenge, we employed a novel Beclin 1 delivery manner by constructing a functional protein (Trx-pHLIP-Beclin 1, TpB) composed of a thioredoxin (Trx) tag, a pH low insertion peptide (pHLIP), and an evolutionarily conserved motif of Beclin 1. This protein could effectively transport Beclin 1 to breast and ovarian cancer cell lines under weakly acidic conditions (pH 6.5), markedly inhibit tumor cell growth and proliferation, and induce obvious autophagy. Furthermore, the in vivo antitumor efficacy of the functional Beclin 1 against an SKOV3 xenograft tumor mouse model was tested via intravenous injection. TpB preferentially accumulated in tumors and exhibited a significantly higher tumor growth inhibition than the nontargeted Beclin 1 control, whereas no overt side effects were observed. Taken together, this study sheds light on the potential application of TpB as a highly efficient yet safe antitumor agent for cancer treatment.
KW - anticancer efficacy
KW - autophagy induction
KW - biological synthesis
KW - functional Beclin 1
KW - pHLIP
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U2 - 10.1021/acsami.7b17454
DO - 10.1021/acsami.7b17454
M3 - Article
C2 - 29359549
AN - SCOPUS:85042083362
VL - 10
SP - 5227
EP - 5239
JO - ACS Applied Materials and Interfaces
JF - ACS Applied Materials and Interfaces
SN - 1944-8244
IS - 6
ER -