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      Trailing TRAIL Resistance: Novel Targets for TRAIL Sensitization in Cancer Cells

      review-article
      1 , 1 , *
      Frontiers in Oncology
      Frontiers Media S.A.
      TRAIL, cancer, apoptosis, TRAIL-resistance, DR4, DR5

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          Abstract

          Resistance to chemotherapeutic drugs is the major hindrance in the successful cancer therapy. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) family of ligands, which initiates apoptosis in cancer cells through interaction with the death receptors DR4 and DR5. TRAIL is perceived as an attractive chemotherapeutic agent as it specifically targets cancer cells while sparing the normal cells. However, TRAIL therapy has a major limitation as a large number of the cancer develop resistance toward TRAIL and escape from the destruction by the immune system. Therefore, elucidation of the molecular targets and signaling pathways responsible for TRAIL resistance is imperative for devising effective therapeutic strategies for TRAIL resistant cancers. Although, various molecular targets leading to TRAIL resistance are well-studied, recent studies have implicated that the contribution of some key cellular processes toward TRAIL resistance need to be fully elucidated. These processes primarily include aberrant protein synthesis, protein misfolding, ubiquitin regulated death receptor expression, metabolic pathways, epigenetic deregulation, and metastasis. Novel synthetic/natural compounds that could inhibit these defective cellular processes may restore the TRAIL sensitivity and combination therapies with such compounds may resensitize TRAIL resistant cancer cells toward TRAIL-induced apoptosis. In this review, we have summarized the key cellular processes associated with TRAIL resistance and their status as therapeutic targets for novel TRAIL-sensitizing agents.

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          Most cited references163

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          Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis.

          We report here that BID, a BH3 domain-containing proapoptotic Bcl2 family member, is a specific proximal substrate of Casp8 in the Fas apoptotic signaling pathway. While full-length BID is localized in cytosol, truncated BID (tBID) translocates to mitochondria and thus transduces apoptotic signals from cytoplasmic membrane to mitochondria. tBID induces first the clustering of mitochondria around the nuclei and release of cytochrome c independent of caspase activity, and then the loss of mitochondrial membrane potential, cell shrinkage, and nuclear condensation in a caspase-dependent fashion. Coexpression of BclxL inhibits all the apoptotic changes induced by tBID. Our results indicate that BID is a mediator of mitochondrial damage induced by Casp8.
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            Targeting cellular metabolism to improve cancer therapeutics

            The metabolic properties of cancer cells diverge significantly from those of normal cells. Energy production in cancer cells is abnormally dependent on aerobic glycolysis. In addition to the dependency on glycolysis, cancer cells have other atypical metabolic characteristics such as increased fatty acid synthesis and increased rates of glutamine metabolism. Emerging evidence shows that many features characteristic to cancer cells, such as dysregulated Warburg-like glucose metabolism, fatty acid synthesis and glutaminolysis are linked to therapeutic resistance in cancer treatment. Therefore, targeting cellular metabolism may improve the response to cancer therapeutics and the combination of chemotherapeutic drugs with cellular metabolism inhibitors may represent a promising strategy to overcome drug resistance in cancer therapy. Recently, several review articles have summarized the anticancer targets in the metabolic pathways and metabolic inhibitor-induced cell death pathways, however, the dysregulated metabolism in therapeutic resistance, which is a highly clinical relevant area in cancer metabolism research, has not been specifically addressed. From this unique angle, this review article will discuss the relationship between dysregulated cellular metabolism and cancer drug resistance and how targeting of metabolic enzymes, such as glucose transporters, hexokinase, pyruvate kinase M2, lactate dehydrogenase A, pyruvate dehydrogenase kinase, fatty acid synthase and glutaminase can enhance the efficacy of common therapeutic agents or overcome resistance to chemotherapy or radiotherapy.
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              Links between metabolism and cancer.

              Chi Dang (2012)
              Metabolism generates oxygen radicals, which contribute to oncogenic mutations. Activated oncogenes and loss of tumor suppressors in turn alter metabolism and induce aerobic glycolysis. Aerobic glycolysis or the Warburg effect links the high rate of glucose fermentation to cancer. Together with glutamine, glucose via glycolysis provides the carbon skeletons, NADPH, and ATP to build new cancer cells, which persist in hypoxia that in turn rewires metabolic pathways for cell growth and survival. Excessive caloric intake is associated with an increased risk for cancers, while caloric restriction is protective, perhaps through clearance of mitochondria or mitophagy, thereby reducing oxidative stress. Hence, the links between metabolism and cancer are multifaceted, spanning from the low incidence of cancer in large mammals with low specific metabolic rates to altered cancer cell metabolism resulting from mutated enzymes or cancer genes.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/197102
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                02 April 2015
                2015
                : 5
                : 69
                Affiliations
                [1] 1Cell Death Research Laboratory, Division of Endocrinology, CSIR-Central Drug Research Institute , Lucknow, India
                Author notes

                Edited by: Gerry Melino, Medical Research Council, UK

                Reviewed by: Alessandro Rufini, University of Leicester, UK; Maria Rosa Ciriolo, Università degli Studi di Roma Tor Vergata, Italy

                *Correspondence: Durga Prasad Mishra, Scientist Cell Death Research Laboratory, Endocrinology Division, CSIR-Central Drug Research Institute, Life Science South Lab No 106, B.S. 10/1, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow-226031, India e-mail: dpm@ 123456cdri.res.in

                This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Oncology.

                Article
                10.3389/fonc.2015.00069
                4382980
                25883904
                edb286b5-042e-43c2-8a6a-a311c030dcaa
                Copyright © 2015 Trivedi and Mishra.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 05 December 2014
                : 09 March 2015
                Page count
                Figures: 3, Tables: 4, Equations: 0, References: 213, Pages: 20, Words: 15206
                Funding
                Funded by: Department of Science and Technology
                Award ID: GAP-00 56
                Funded by: CSIR Network Project
                Award ID: BSC0103
                Funded by: Council of Scientific and Industrial Research, New Delhi
                Categories
                Oncology
                Review Article

                Oncology & Radiotherapy
                trail,cancer,apoptosis,trail-resistance,dr4,dr5
                Oncology & Radiotherapy
                trail, cancer, apoptosis, trail-resistance, dr4, dr5

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