Targeted inhibition of ACLY expression to reverse the resistance of sorafenib in hepatocellular carcinoma

Resistance to sorafenib has been documented in hepatocellular carcinoma (HCC) patients. We investigated: (i) the correlation between adenosine triphosphate citrate lyase (ACLY) expression and sorafenib resistance in HCC; and (ii) if targeted inhibition could reverse sorafenib resistance. Samples of HCC tissue were obtained from patients and ACLY expression was measured. PET/CT was employed to measure maximum standard unit value (SUV(max)) in HCC patients before and after sorafenib treatment. Using HepG2 cells, we created a sorafenib-resistant cell line. Glucose metabolism and lipid synthesis in HCC cells were tested using (14)C-glucose. Disulfide-crosslinked polyethylenimine (SS-PEI)-mediated plasmid transfection was carried out, followed by creation of an HCC model in mice. SUV(max) of HCC lesions was closely related to ACLY expression. Patients with high ACLY expression were not sensitive to sorafenib therapy. Lipid metabolism was more active in sorafenib-resistant HCC cells. ACLY expression was higher in sorafenib-resistant cells and HCC-cell sensitivity to sorafenib increased after ACLY-knockout. The latter reversed sorafenib resistance in HCC cells more significantly under hypoxic conditions. SS-PEI/proline-modified short hairpin-(psh)RNA-ACLY plus sorafenib inhibited the growth of drug-resistant cells significantly. These data suggest that ACLY downregulation can reverse sorafenib resistance, and that SS-PEI can be used to mediate shRNA-ACLY transfection in HCC treatment.