TY - JOUR
T1 - Development of a novel prostate apoptosis response-4 (Par-4) protein entity with an extended duration of action for therapeutic treatment of cancer
AU - Kim, Kyungbo
AU - Araujo, Pereira
AU - Hebbar, Nikhil
AU - Zhou, Ziyuan
AU - Zheng, Xirong
AU - Zheng, Fang
AU - Rangnekar, Vivek M.
AU - Zhan, Chang Guo
N1 - Publisher Copyright:
© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].
PY - 2019/12/13
Y1 - 2019/12/13
N2 - Prostate apoptosis response-4 (Par-4) is a tumor suppressor which protects against neoplastic transformation. Remarkably, Par-4 is capable of inducing apoptosis selectively in cancer cells without affecting the normal cells. In this study, we found that recombinant Par-4 protein had limited serum persistence in mice that may diminish its anti-tumor activity in vivo. To improve the in vivo performance of the short-lived Par-4 protein, we aimed to develop a novel, long-lasting form of Par-4 with extended sequence, denoted as Par-4Ex, without affecting the desirable molecular function of the natural Par-4. We demonstrate that the Par-4Ex protein entity, produced by using the Escherichia coli expression system suitable for large-scale production, fully retains the desirable pro-apoptotic activity of Par-4 protein, but with ~7-fold improved biological half-life. Further in vivo tests confirmed that, due to the prolonged biological half-life, the Par-4Ex protein is indeed more potent in suppressing metastatic tumor growth in mice.
AB - Prostate apoptosis response-4 (Par-4) is a tumor suppressor which protects against neoplastic transformation. Remarkably, Par-4 is capable of inducing apoptosis selectively in cancer cells without affecting the normal cells. In this study, we found that recombinant Par-4 protein had limited serum persistence in mice that may diminish its anti-tumor activity in vivo. To improve the in vivo performance of the short-lived Par-4 protein, we aimed to develop a novel, long-lasting form of Par-4 with extended sequence, denoted as Par-4Ex, without affecting the desirable molecular function of the natural Par-4. We demonstrate that the Par-4Ex protein entity, produced by using the Escherichia coli expression system suitable for large-scale production, fully retains the desirable pro-apoptotic activity of Par-4 protein, but with ~7-fold improved biological half-life. Further in vivo tests confirmed that, due to the prolonged biological half-life, the Par-4Ex protein is indeed more potent in suppressing metastatic tumor growth in mice.
KW - Par-4
KW - biological half-life
KW - metastatic cancer
KW - protein engineering
KW - therapeutic protein
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U2 - 10.1093/protein/gzz034
DO - 10.1093/protein/gzz034
M3 - Article
C2 - 31711233
AN - SCOPUS:85076449298
SN - 1741-0126
VL - 32
SP - 159
EP - 166
JO - Protein Engineering, Design and Selection
JF - Protein Engineering, Design and Selection
IS - 3
ER -