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Perturbation of one of these mechanisms is sufficient to overcome TRAIL resistance and sensitise cancer cells to TRAIL-induced apoptosis. In contrast, most cancer cells overexpress one of anti-apoptotic proteins leading to resistance development. Downregulation of one of these antiapoptotic proteins is not sufficient to sensitize non-transformed cells to apoptosis, reflecting the multiple mechanisms involved in TRAIL resistance in normal cells. Secondly, they upregulate several anti-apoptotic proteins including Inhibitors of Apoptosis Proteins (IAP), cellular FLICE-like inhibitory protein (cFLIP) and Bcl-2. Firstly, they overexpress TRAIL-R3 decoy receptors while downregulate apoptosis-mediated DR4/5. Interestingly, normal non-transformed cells resist TRAIL’s proapoptotic action via different resistance mechanisms. In some instances, the activated caspase 8 truncates the mitochondrial B-cell lymphoma 2 (Bcl-2)-related proapoptotic protein (Bid) triggering the intrinsic or the mitochondrial pathway of apoptosis. Several proteases and nucleases are then activated, causing protein destruction, nuclear fragmentation, collapse of cytoplasmic membrane, and formation of apoptotic bodies. The complex of DRs with FADD and caspase 8/10 forms what’s called Death Inducing Signaling Cascade (DISC) which is the trigger of apoptotic events that ends with activation of the executioner caspases 3/7. Upon the binding to DR4 or DR5, TRAIL recruits Fas Associated Death Domain (FADD) at the cytoplasmic death domain (DD) of the receptors, causing activation of the initiator caspases, such as caspase 8 and caspase 10.
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TRAIL is a cytokine belonging to the TNF superfamily that mainly activates the extrinsic pathway of apoptosis upon binding to its cognate receptors, known as death receptors (DRs) including DR4 and DR5. The use of tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) as an anticancer therapy has attracted the attention of the scientific community and created great excitement because it selectively targets cancer cells with minimal or no effects on noncancerous counterparts. To the best of our knowledge, this is the first study to mechanistically report the cancer chemosensitisation potential of curcumin in kidney cancer cells via induction of let-7C. Overall, curcumin targeted ACHN cell cycle and cellular metabolism by promoting the differential expression of let-7C. Curcumin also suppressed the expression of the overexpressed proteins when added to the antagomir transfected cells. Further, it overexpressed the expression of the two key glycolysis regulating proteins including hypoxia-inducible factor 1-alpha (HIF-1α) and pyruvate dehydrogenase kinase 1 (PDK1). Transfecting ACHN cells with a let-7C antagomir significantly increased the expression of several cell cycle protein, namely beta (β)-catenin, cyclin dependent kinase (CDK)1/2/4/6 and cyclin B/D. Curcumin deregulated the expression of apoptosis-regulating micro Ribonucleic Acid (miRNAs), most notably, let-7C. This study aimed to employ curcumin to sensitise TRAIL-resistant kidney cancerous ACHN cells, as well as to gain insight into the molecular mechanisms of TRAIL sensitization. However, clinical studies disappointingly showed the emergence of resistance against TRAIL. The use of tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) as an anticancer therapy has attracted the attention of the scientific community and created great excitement due to its selectivity in targeting cancerous cells with no toxic impacts on normal tissues. Such therapies have entered a golden era due to advancements in research, breakthroughs in scientific knowledge, and a better understanding of cancer therapy mechanisms, which significantly improve the survival rates and life expectancy of patients. Targeted therapies are the most attractive options in the treatment of different tumours, including kidney cancers.