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Mechanisms of resistance to TRAIL-induced apoptosis in cancer.
Cancer Gene Ther. 2005 Mar; 12(3):228-37.CG

Abstract

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as a potential anticancer agent. However, considerable numbers of cancer cells, especially some highly malignant tumors, are resistant to apoptosis induction by TRAIL, and some cancer cells that were originally sensitive to TRAIL-induced apoptosis can become resistant after repeated exposure (acquired resistance). Understanding the mechanisms underlying such resistance and developing strategies to overcome it are important for the successful use of TRAIL for cancer therapy. Resistance to TRAIL can occur at different points in the signaling pathways of TRAIL-induced apoptosis. Dysfunctions of the death receptors DR4 and DR5 due to mutations can lead to resistance. The adaptor protein Fas-associated death domain (FADD) and caspase-8 are essential for assembly of the death-inducing signaling complex, and defects in either of these molecules can lead to TRAIL resistance. Overexpression of cellular FADD-like interleukin-1beta-converting enzyme-inhibitory protein (cFLIP) correlates with TRAIL resistance in several types of cancer. Overexpression of Bcl-2 or Bcl-X(L), loss of Bax or Bak function, high expression of inhibitor of apoptosis proteins, and reduced release of second mitochondria-derived activator of caspases (Smac/Diablo) from the mitochondria to the cytosol have all been reported to result in TRAIL resistance in mitochondria-dependent type II cancer cells. Finally, activation of different subunits of mitogen-activated protein kinases or nuclear factor-kappa B can lead to development of either TRAIL resistance or apoptosis in certain types of cancer cells.

Authors+Show Affiliations

Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.No affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

15550937

Citation

Zhang, Lidong, and Bingliang Fang. "Mechanisms of Resistance to TRAIL-induced Apoptosis in Cancer." Cancer Gene Therapy, vol. 12, no. 3, 2005, pp. 228-37.
Zhang L, Fang B. Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther. 2005;12(3):228-37.
Zhang, L., & Fang, B. (2005). Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Therapy, 12(3), 228-37.
Zhang L, Fang B. Mechanisms of Resistance to TRAIL-induced Apoptosis in Cancer. Cancer Gene Ther. 2005;12(3):228-37. PubMed PMID: 15550937.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanisms of resistance to TRAIL-induced apoptosis in cancer. AU - Zhang,Lidong, AU - Fang,Bingliang, PY - 2004/11/20/pubmed PY - 2005/6/18/medline PY - 2004/11/20/entrez SP - 228 EP - 37 JF - Cancer gene therapy JO - Cancer Gene Ther VL - 12 IS - 3 N2 - The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is regarded as a potential anticancer agent. However, considerable numbers of cancer cells, especially some highly malignant tumors, are resistant to apoptosis induction by TRAIL, and some cancer cells that were originally sensitive to TRAIL-induced apoptosis can become resistant after repeated exposure (acquired resistance). Understanding the mechanisms underlying such resistance and developing strategies to overcome it are important for the successful use of TRAIL for cancer therapy. Resistance to TRAIL can occur at different points in the signaling pathways of TRAIL-induced apoptosis. Dysfunctions of the death receptors DR4 and DR5 due to mutations can lead to resistance. The adaptor protein Fas-associated death domain (FADD) and caspase-8 are essential for assembly of the death-inducing signaling complex, and defects in either of these molecules can lead to TRAIL resistance. Overexpression of cellular FADD-like interleukin-1beta-converting enzyme-inhibitory protein (cFLIP) correlates with TRAIL resistance in several types of cancer. Overexpression of Bcl-2 or Bcl-X(L), loss of Bax or Bak function, high expression of inhibitor of apoptosis proteins, and reduced release of second mitochondria-derived activator of caspases (Smac/Diablo) from the mitochondria to the cytosol have all been reported to result in TRAIL resistance in mitochondria-dependent type II cancer cells. Finally, activation of different subunits of mitogen-activated protein kinases or nuclear factor-kappa B can lead to development of either TRAIL resistance or apoptosis in certain types of cancer cells. SN - 0929-1903 UR - https://www.unboundmedicine.com/medline/citation/15550937/Mechanisms_of_resistance_to_TRAIL_induced_apoptosis_in_cancer_ L2 - https://doi.org/10.1038/sj.cgt.7700792 DB - PRIME DP - Unbound Medicine ER -