Atorvastatin induces MicroRNA-145 expression in HEPG2 cells via regulation of the PI3K/AKT signalling pathway

• Published in: Chemico-biological interactions Vol. 287; pp. 32 - 40
• Main Authors: Docrat, Taskeen Fathima, Nagiah, Savania, Krishnan, Anand, Naidoo, Dhaneshree B., Chuturgoon, Anil A.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.05.2018
• Subjects: Atorvastatin; HepG2; miRNA-145; PI3K/Akt; Atorvastatin; HepG2; miRNA-145; PI3K/Akt
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2018.04.005

The use of statins as a potential cancer drug has been investigated; however the molecular mechanisms involved in their anti-oxidant, anti-proliferative and anti-cancer effects remain elusive. In our study, we investigated the involvement of downstream mevalonate products that mediate the anti-oxidant and anti-proliferative effects of Atorvastatin (Ato), and its effect on microRNA-145 expression in HepG2 hepatocellular carcinoma cells. An amorphous soluble form of Ato was prepared and found to be cytotoxic in vitro [IC50 (1.2 mM); 48 h]. Atorvastatin induced a dose-dependent increase in cell mortality with a concomitant depletion of intracellular ATP levels (p = 0.005); significantly increased extracellular nitrite levels (p = 0.001) and decreased lipid peroxidation (p = 0.0097) despite a decrease in GSH. The intrinsic apoptotic pathway was activated via increased caspase −9 (p < 0.0001) and −3/7 (p = 0.0003) activities. Increased protein expression of pGSK3-(α/β) (p = 0.0338), p53 (p = 0.0032), Mdm2 (p < 0.0001), with significantly diminished levels of PI3K (p = 0.0013), pAKT (p = 0.0035), and Akt (p = 0.0077), indicated that Ato-mediated cell death occurred via inhibition of the PI3K/Akt pathway. Additionally, the expression of PI3K (p = 0.0001) and c-myc (p = 0.0127) were also downregulated, whilst and miRNA-145 (p = 0.0156) was upregulated. In conclusion our data strongly indicates a plausible mechanism involved in the cytotoxic effects of Ato and is the first study to show that Ato modulates miR-145 expression in hepatocytes. ≤  •Atorvastatin (Ato) increased liver cell mortality and decreased [ATP].•Ato increased activites of caspases- 9,3 and 7.•Ato increased protein expression of pGSK3, p53 and Mdm2.•Ato decreased protein expression of PI3K, pAKT and AKT.•Ato modulates expression of miR-145.