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Journal of cellular physiology v.233 no.10, 2018년, pp.6470 - 6485  

Down‐regulation of intracellular anti‐apoptotic proteins, particularly c‐FLIP by therapeutic agents; the novel view to overcome resistance to TRAIL

Hassanzadeh, Ali (Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran ) ; Farshdousti Hagh, Majid (Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran ) ; Alivand, Mohammad Reza (Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran ) ; Akbari, Ali Akbar Movassaghpour (Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran ) ; Shams Asenjan, Karim (Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran ) ; Saraei, Raedeh (Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran ) ; Solali, Saeed (Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran ) ;
  • 초록  

    Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL or Apo2L) is a member of the tumor necrosis factor (TNF) superfamily that induces apoptosis in different types of cancer cells via activation of caspase cascade. TRAIL interacts with its cognate receptors that placed on cancer cells surface, including TRAIL‐R1 (death receptor 4, DR4), TRAIL‐R2 (death receptor 5, DR5), TRAIL‐R3 (decoy receptor 1, DcR1), TRAIL‐R4 (decoy receptor 2, DcR2), and osteoprotegerin (OPG). Despite high apoptosis‐inducing ability of TRAIL, various cancerous cells gain resistance to TRAIL gradually, and consequently TRAIL potential for apoptosis stimulation in these cells diminishes intensely. According to diverse ranges of examinations, intracellular anti‐apoptotic proteins, such as cellular‐FLICE inhibitory protein (c‐FLIP), apoptosis inhibitors (IAPs), myeloid cell leukemia sequence 1 (MCL‐1), BCL‐2, BCL‐XL, and survivin play key role in cancer cells resistance to TRAIL. These proteins attenuate cancer cells sensitivity to TRAIL via various functions, importantly through caspase cascade suppression. The c‐FLIP avoids from caspase 8 activation by FADD via binding to caspase 8 cleavage of FADD. Moreover, it activates signaling pathways that involved in cancer cells survival and proliferation. Intriguingly, it appears that the down‐regulation of intracellular anti‐apoptotic proteins, particularly c‐FLIP is effectiveness goal for TRAIL‐resistant cancers therapy, because their up‐regulation in association with poor prognosis has been observed in various types of TRAIL‐resistant cancers. In this review, we tried to collect and examine investigations that researchers have been able to sensitize cancer cells to TRAIL through targeting of c‐FLIP alone or with other intracellular anti‐apoptotic proteins directly or indirectly. It seems that co‐treatment of resistant cells by TRAIL with other therapeutic agents with the aim of intracellular anti‐apoptotic proteins inhibition is hopeful and attractive approach to overcome various TRAIL‐resistant cancers.


  • 주제어

    c‐FLIP .   intracellular anti‐apoptotic proteins .   resistance .   TRAIL.  

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