Downregulation of telomerase activity by diclofenac and curcumin is associated with cell cycle arrest and induction of apoptosis in colon cancer.
Uncontrolled cell proliferation is the hallmark of cancer, and cancer cells have typically acquired damage to genes that directly regulate their cell cycles. The synthesis of DNA onto the end of chromosome during the replicative phase of cell cycle by telomerase may be necessary for unlimited proliferation of cells. Telomerase, a ribonucleoprotein enzyme is considered as a universal therapeutic target of cancer because of its preferential expression in cancer cells and its presence in 90 % of tumors. We studied the regulation of telomerase and telomerase reverse transcriptase catalytic subunit (TERT) by diclofenac and curcumin, alone and also in combination, in 1, 2-dimethylhydrazine dihydrochloride-induced colorectal cancer in rats. The relationship of telomerase activity with tumors suppressor proteins (p51, Rb, p21), cell cycle machinery, and apoptosis was also studied. Telomerase is highly expressed in DMH group and its high activity is associated with increased TERT expression. However, telomerase is absent or is present at lower levels in normal tissue. CDK4, CDK2, cyclin D1, and cyclin E are highly expressed in DMH as assessed by RT-PCR, qRT-PCR, Western blot, and immunofluorescence analysis. Diclofenac and curcumin overcome these carcinogenic effects by downregulating telomerase activity, diminishing the expression of TERT, CDK4, CDK2, cyclin D1, and cyclin E. The anticarcinogenic effects shown after the inhibition of telomerase activity by diclofenac and curcumin may be associated with upregulation of tumor suppressor proteins p51, Rb, and p21, whose activation induces the cells cycle arrest and apoptosis.
Department of Biophysics, Panjab University, Chandigarh, 160014, India.
Chandan
C
Rana
Honit
H
Piplani
Vivek
V
Vaish
Bimla
B
Nehru
S N
SN
Sanyal
D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003474:Curcumin / Q000008:administration & dosage; D019938:Cyclin D1 / Q000096:biosynthesis*; D019927:Cyclin E / Q000096:biosynthesis*; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis*; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis*; D004008:Diclofenac / Q000008:administration & dosage; D006801:Humans; D015513:Oncogene Proteins / Q000096:biosynthesis*; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins; D019938:Cyclin D1; D004008:Diclofenac; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; C509186:TERT protein, human; D019098:Telomerase; D003474:Curcumin