A recombinant cell-permeable p53 fusion protein is selectively stabilized under hypoxia and inhibits tumor cell growth.
More than 50% of human tumors contain a mutation in p53. Over 90% of tumors are solid tumors. Solid tumors have low oxygenated regions, called hypoxic regions where the tumor cells are more resistant to radio- and chemo-therapy than their well-oxygenated counterparts. In this study, we constructed a cell-permeable p53 fusion protein with selective stability in the hypoxic region. The fusion protein contained the TAT peptide for transduction across membranes, the oxygen-dependent degradation domain of hypoxia-inducible factor-1alpha and wild-type p53. This protein was effectively delivered into tumor cells where it exerted anticancer activity leading to the inhibition of cancer cell growth in vitro and the reduction of tumor weight in vivo. Hence, the fusion protein can be a novel protein drug for antitumor therapies, especially for hypoxic tumor cells.
Yu
Zhao
Z
Beijing Institute of Pharmacology and Toxicology, 27, Taiping Road, Haidian District, Beijing 100850, China.
Wu
Junhua
J
Wu
Shaoping
S
Jia
Peiyuan
P
Tong
Ying
Y
Wu
Xumin
X
Wang
Yuxia
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology; D055550:Protein Stability; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology
D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D054322:tat Gene Products, Human Immunodeficiency Virus; C497137:tat peptide (47-57), Human immunodeficiency virus 1