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 (SUVmax) 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 14C-glucose.
Disulfide-crosslinked
polyethylenimine (SS-PEI)-mediated plasmid transfection was carried out, followed by creation of an HCC model in mice. SUVmax 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.