Apoptosis inhibitor TRIAP1 is a novel effector of drug resistance
- 19 May 2015
- journal article
- Published by Spandidos Publications in Oncology Reports
- Vol. 34 (1), 415-422
- https://doi.org/10.3892/or.2015.3988
Abstract
TP53-regulated inhibitor of apoptosis 1 (TRIAP1) is a novel apoptosis inhibitor that binds HSP70 in the cytoplasm and blocks the formation of the apoptosome and caspase-9 activation. TRIAP1 has been shown to be upregulated in many types of cancers; however, its role remains elusive. We determined the TRIAP1 mRNA levels in a panel of human tissues and found its expression to be ubiquitous. Normal breast, as well as non-tumorigenic breast cells, exhibited lower TRIAP1 mRNA levels than breast cancer cells or their drug-resistant derivatives. TRIAP1 is a small, evolutionarily conserved protein that is 76 amino acids long. We found that yeast cells, in which the TRIAP1 homologue was knocked out, had increased sensitivity to doxorubicin. Equally, RNA interference in breast cancer drug-resistant cells demonstrated that downregulation of TRIAP1 impaired cell growth in the presence of doxorubicin. As expected, caspase-9 activation was diminished after overexpression of TRIAP1 in drug-resistant cells. Importantly, stable transfections of a TRIAP1 expression plasmid in CAL51 cells led to a marked increase in the number of doxorubicin‑resistant clones, that was abolished when cells expressed hairpins targeting TRIAP1. In addition, we showed that TRIAP1 expression was also triggered by estrogen deprivation in MCF-7 cells. Although both polyclonal and monoclonal antibodies generated for the present study failed to robustly detect TRIAP1, we demonstrated that TRIAP1 represents a novel marker for drug resistance in breast cancer cells and it may be used in the stratification of breast cancer patients once a suitable antibody has been developed. Equally, these studies open potential drug development strategies for blocking TRIAP1 activity and avoiding drug resistance.Keywords
This publication has 35 references indexed in Scilit:
- Recent advances in apoptosis, mitochondria and drug resistance in cancer cellsBiochimica et Biophysica Acta (BBA) - Bioenergetics, 2011
- Mdm35p imports Ups proteins into the mitochondrial intermembrane space by functional complex formationThe EMBO Journal, 2010
- Apoptosis and cancer: the genesis of a research fieldNature Reviews Cancer, 2009
- Apoptosis: A Review of Programmed Cell DeathToxicologic Pathology, 2007
- Wild-Type p53: Tumors Can't Stand ItCell, 2007
- Restoring p53-mediated apoptosis in cancer cells: New opportunities for cancer therapyDrug Resistance Updates, 2006
- Defects of the apoptotic pathway as therapeutic target against cancerDrug Resistance Updates, 2005
- p53CSV, a Novel p53-Inducible Gene Involved in the p53-Dependent Cell-Survival PathwayCancer Research, 2005
- Inhibitor of apoptosis proteins: new therapeutic targets in hematological cancer?Leukemia, 2004
- IAP proteins: blocking the road to death's doorNature Reviews Molecular Cell Biology, 2002