TY - JOUR
T1 - Introduction of hypoxia-targeting p53 fusion protein for the selective therapy of non-small cell lung cancer
AU - Zhao, Yu
AU - Wu, Shaoping
AU - Wu, Junhua
AU - Jia, Peiyuan
AU - Gao, Shan
AU - Yan, Xiangdong
AU - Wang, Yuxia
PY - 2011/1/1
Y1 - 2011/1/1
N2 - Non-small cell lung cancer (NSCLC), which accounts for ∼85% of lung cancer, is the major cause of malignancy mortality around the world. TP53 dysfunction and hypoxia are the typical biological features of the diverse solid tumors, including NSCLC. To develop an effective and low cytotoxic biological agent for targeted therapy, a p53 fusion protein, which was conjugated with the minimum motif of oxygen-dependent degradation domain (ODD) and the basic domain of TAT of HIV-1 named as TAT-ODD-p53, was evaluated for the treatment of NSCLC established by grafting H1299 cell line in which TP53 is homozygously deleted. We provide the evidence that this p53 fusion protein could significantly induce the cell cycle arrest and/or apoptosis to inhibit H1299 cells' growth via p53-dependent pathways, including upregulation of p21 expression and activation of pro-caspase-3, especially under hypoxia in vitro. The results in vivo indicated that this protein could selectively accumulate in the low oxygen tension areas of solid tumor tissues, inhibiting tumor growth via a similar mechanism to that in vitro. No obvious side effects were observed. Therefore, this recombinant p53 protein is likely to become a good candidate for targeted therapy of NSCLC.
AB - Non-small cell lung cancer (NSCLC), which accounts for ∼85% of lung cancer, is the major cause of malignancy mortality around the world. TP53 dysfunction and hypoxia are the typical biological features of the diverse solid tumors, including NSCLC. To develop an effective and low cytotoxic biological agent for targeted therapy, a p53 fusion protein, which was conjugated with the minimum motif of oxygen-dependent degradation domain (ODD) and the basic domain of TAT of HIV-1 named as TAT-ODD-p53, was evaluated for the treatment of NSCLC established by grafting H1299 cell line in which TP53 is homozygously deleted. We provide the evidence that this p53 fusion protein could significantly induce the cell cycle arrest and/or apoptosis to inhibit H1299 cells' growth via p53-dependent pathways, including upregulation of p21 expression and activation of pro-caspase-3, especially under hypoxia in vitro. The results in vivo indicated that this protein could selectively accumulate in the low oxygen tension areas of solid tumor tissues, inhibiting tumor growth via a similar mechanism to that in vitro. No obvious side effects were observed. Therefore, this recombinant p53 protein is likely to become a good candidate for targeted therapy of NSCLC.
KW - Hypoxia
KW - Non-small cell lung cancer
KW - Oxygen-dependent degradation domain
KW - P53
KW - Solid tumor
KW - TAT
KW - Targeted therapy
UR - http://www.scopus.com/inward/record.url?scp=78751537820&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78751537820&partnerID=8YFLogxK
U2 - 10.4161/cbt.11.1.13960
DO - 10.4161/cbt.11.1.13960
M3 - Review article
C2 - 21248471
AN - SCOPUS:78751537820
SN - 1538-4047
VL - 11
SP - 95
EP - 107
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 1
ER -