Human Serum Albumin and the p53-Derived Peptide Fusion Protein Promotes Cytotoxicity Irrespective of p53 Status in Cancer Cells

Molecular Pharmaceutics
Ivana RoscoeZhiyu Li

Abstract

Human serum albumin (HSA) fusion protein is a viable and effective approach to target and inhibit essential intracellular pathways. It has previously been shown that an HSA fusion protein containing a p53-reactivating peptide (rHSA-p53i) retains the binding activity to MDM2 and MDMX, resulting in p53 transcription-dependent apoptosis. Here, we demonstrate that rHSA-p53i is able to bind and neutralize anti-apoptotic Bcl-2 family proteins, Bcl-xL and Mcl-1. This interaction displaces pro-apoptotic Bak and subsequently leads to intrinsic apoptosis via mimicking a p53 transcription-independent pathway. Cytotoxicity induced by rHSA-p53i, via p53 transcription dependent and independent apoptotic pathways, is irrespective of the p53 status in MDA-MB-231, HeLa, and SJSA-1 cells possessing either mutant, deficient, or wild-type p53. The therapeutic potential is also confirmed by treating SJSA-1 and MDA-MB-231 xenograft mouse tumors with rHSA-p53i. These data reveal that rHSA-p53i interferes with at least four intracellular targets, making it a viable therapeutic protein for the treatment of a variety of cancers, as well as a carrier to deliver fatty acid-modified chemotherapeutics.

References

Apr 23, 2003·The Journal of Immunology : Official Journal of the American Association of Immunologists·Andreas WunderChristoph Fiehn
Aug 15, 2006·The Journal of Biological Chemistry·Baoli HuJiandong Chen
Nov 15, 2008·Biochimica Et Biophysica Acta·Angelina V Vaseva, Ute M Moll
May 2, 2009·Nature·Douglas R Green, Guido Kroemer
Jul 31, 2009·Oncogene·T Ni Chonghaile, A Letai
Jul 1, 2010·Expert Opinion on Drug Delivery·Elena NeumannChristoph Fiehn
Feb 26, 2011·Current Pharmaceutical Design·Hongmei LiCraig L Duvall
Jul 19, 2011·Developmental Cell·Jean-Claude Martinou, Richard J Youle
Jul 20, 2011·Proceedings of the National Academy of Sciences of the United States of America·Samantha R OakesGeoffrey J Lindeman
Oct 1, 2011·Journal of Controlled Release : Official Journal of the Controlled Release Society·Bakheet Elsadek, Felix Kratz
Mar 14, 2012·Oncotarget·Dongsheng PeiJunnian Zheng
Dec 21, 2012·Chemical Biology & Drug Design·David J CraikDavid Price
Aug 28, 2013·Biochemistry·Hongwei YaoYingang Feng
Dec 18, 2013·Biochemical and Biophysical Research Communications·Jae-Sun ShinSeung-Wook Chi
Mar 19, 2014·Journal of Controlled Release : Official Journal of the Controlled Release Society·Felix Kratz
Mar 26, 2014·Biomacromolecules·Alice W Du, Martina H Stenzel
Apr 18, 2014·Nature Reviews. Cancer·Kathryn T BiegingLaura D Attardi
Apr 22, 2014·FEBS Letters·Anna ComelGiannino Del Sal
Aug 28, 2014·Frontiers in Physiology·Angelica M MerlotDes R Richardson
Dec 3, 2014·Drug Discovery Today·Keld Fosgerau, Torsten Hoffmann
Feb 13, 2015·Frontiers in Immunology·Kine Marita Knudsen SandJan Terje Andersen
Jul 17, 2015·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·William R Strohl
Jul 19, 2015·Trends in Molecular Medicine·Drazen Raucher, Jung Su Ryu
Mar 1, 2016·Molecular and Cellular Therapies·Maja Thim LarsenKenneth A Howard
May 6, 2016·Annual Review of Biochemistry·Andreas C Joerger, Alan R Fersht
Nov 27, 2016·Oncotarget·Karin HientzThomas Efferth
Apr 10, 2017·Journal of Molecular Biology·Xuetian YueWenwei Hu
Jan 1, 2018·Cell Death and Differentiation·Jerry M Adams, Suzanne Cory

❮ Previous
Next ❯

Citations

Jul 21, 2021·International Journal of Biological Macromolecules·Hong-Yu TaoYong-Su Zhen

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

BCL-2 Family Proteins

BLC-2 family proteins are a group that share the same homologous BH domain. They play many different roles including pro-survival signals, mitochondria-mediated apoptosis and removal or damaged cells. They are often regulated by phosphorylation, affecting their catalytic activity. Here is the latest research on BCL-2 family proteins.