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Hepatocellular carcinoma (HCC) has an annual worldwide incidence of 626 000 cases and causes 550 000 deaths per year. Although the mainstay of treatment is surgical resection, for inoperable or metastatic disease, chemotherapy may be offered. The primary agent used is doxorubicin, but response rates are poor (<20%). The unfolded protein response (UPR) is a cytoprotective cellular stress response that enables cells to survive periods of hypoxia and nutrient deprivation. The UPR may confer resistance to anticancer agents and contribute to treatment failure. This study has investigated whether the UPR is activated in HCC and whether this may contribute to doxorubicin resistance.Eighty-six human HCCs were immunohistochemically stained for glucose regulated protein 78, the key marker of UPR activation. An in-vitro model of UPR activation in HepG2 HCC cells was developed by glucose deprived culture. UPR activation was confirmed with western blotting and PCR to show overexpression of glucose regulated protein 78. The relative efficacy of doxorubicin chemotherapy on UPR-activated HepG2 cells was compared with normal HepG2 cells by use of an thiazolyl blue tetrazolium bromide colorimetric assay.Expression of glucose regulated protein 78 was shown in 100% of the HCC samples with 66% showing strong staining. In-vitro UPR activation was achieved with glucose deprivation. UPR activation induced significant resistance to doxorubicin: 34% survival under standard culture conditions versus 58% and 63% for UPR-activated cells in 0.5 and 1 mmol glucose respectively (P=0.00928).The UPR is activated in HCCs and confers resistance to chemotherapy in vitro. UPR activation may contribute to HCC chemoresistance.