Curcumin Sensitises Cancerous Kidney Cells to TRAIL Induced Apoptosis via Let-7C Mediated Deregulation of Cell Cycle Proteins and Cellular Metabolism

Abstract

Targeted therapies are the most attractive options in the treatment of different tumours, including kidney cancers. 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. 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. However, clinical studies disappointingly showed the emergence of resistance against TRAIL. 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. Curcumin deregulated the expression of apoptosis-regulating micro Ribonucleic Acid (miRNAs), most notably, let-7C. 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. 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). Curcumin also suppressed the expression of the overexpressed proteins when added to the antagomir transfected cells. Overall, curcumin targeted ACHN cell cycle and cellular metabolism by promoting the differential expression of let-7C. 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.

The Involvement of Natural Polyphenols in Molecular Mechanisms Inducing Apoptosis in Tumor Cells: A Promising Adjuvant in Cancer Therapy

“…Furthermore, the upregulation of TRAIL, in glioblastoma multiforme [ 165 ], renal [ 164 ], breast [ 163 ], prostate cancer cells [ 166 ] and FasL in hepatocellular carcinoma [ 167 ] plays a key role in curcumin-mediated extrinsic apoptosis. In a recent paper, Obaidi and co-workers demonstrated that curcumin sensitized cancerous kidney cells to TRAIL-induced apoptosis via the Let-7C mediated deregulation of cell cycle proteins and cellular metabolism [ 168 ]. On the other hand, changes in mitochondria function, as well as the p53-dependent bax upregulation in breast [ 169 ] and colon cancer cells [ 36 ] and the bcl-2 down-regulation in laryngeal [ 170 ], breast [ 171 ] and prostate [ 172 ] cancer cells, are the most crucial changes that occur in curcumin-mediated intrinsic apoptosis.…”

The Role of microRNAs in Arsenic-Induced Human Diseases: A Review

“…These functional miRNAs form the RISC via binding to AGO. Finally, the active complex interacts with the 3′-UTR of target mRNA through complementary pairing of base pairings, causing translational repression or RNA degradation (Figure A). − Through this process, miRNAs were involved in a series of cellular processes, including apoptosis, − oxidative stress, cell proliferation, , inflammation, , hematopoiesis, , and tumorigenesis. , …”

“…A particular miRNA can target various mRNAs to induce translational repression or RNA degradation, and one mRNA can be regulated by multiple different miRNAs . By modulating gene expression at the post-translational level, miRNAs play a critical role in a series of cellular processes, including apoptosis, − oxidative stress, cell proliferation, , inflammation, , hematopoiesis, , and tumorigenesis. , Importantly, miRNAs not only have an intracellular function but also stably exist in biological fluids such as saliva, cerebrospinal fluid, plasma, serum, gingival fluid, and urine. − Therefore, circulating miRNAs are considered biomarkers of disease and can regulate gene expression in distal cells or organs. ,, …”

The Effect Of Curcumin On Hypoxia In Tumor Microenvironment As a Regulatory Factor In Cancer

“…Furthermore, let-7C can regulate PDK1 expression through HIF-1α inhibition [ 109 ]. Obaidi et al reported the cancer chemosensitization potential of curcumin through the induction of let-7C on RCC [ 110 ].…”