Background: Sorafenib is a newly established cancer drug found to be an effective systemic treatment for advanced hepatocellular carcinoma (HCC). However, little is known about any potential effectors that modify tumor cell sensitivity towards sorafenib. Here, we present the first evidence that glucose-regulated protein 78 (GRP78) is intimately associated with acquisition of resistance towards sorafenib. Methods: The role of GRP78 in acquisition of resistance towards sorafenib was determined using HepJ5 (a GRP78-overexpressing subline) and HepG2 as its pair-matched control. RNA interference in cancer cells was applied to determine the influence of GRP78 expression on sensitivity to sorafenib treatment. Results: We found that HepG2 cells exhibited higher sensitivity toward sorafenib, with 50% inhibition concentration (IC 50) >20 μΜ for HepJ5 and 4.8 μM for HepG2. Specifically, when HepG2 cells received 20 μM sorafenib treatment for 24 h, over 80% of cells underwent apoptosis compared with only 32% of HepJ5 cells under similar experimental conditions. Similarly, GRP78 knockdown in HepJ5 cells by small interfering RNA (siRNA) technique enhanced the efficacy of sorafenib-mediated cell death. This was reflected by a shift of IC50 values from >20 μM to 4.8 μM. Conclusions: GRP78 is a positive modifier for sorafenib resistance acquisition in HCC and represents a prime target for overcoming sorafenib resistance.
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