Analysis of ABCG2 expression and side population identifies intrinsic drug efflux in the HCC cell line MHCC-97L and its modulation by Akt signaling

Abstract

Active drug efflux by the adenosine triphosphate-binding cassette (ABC) transporter ABCG2 is one of the common mechanisms causing multiple drug resistance in various human cancers. In the intrinsic drug resistance of hepatocellular carcinoma (HCC), the role of ABCG2 is closely associated with 'side population (SP)', a minor subset of cancer stem-like cells with unique capacity to extrude lipophilic dye Hoechst 33342 and many chemotherapeutic agents. In this study, we showed that ABCG2 was intrinsically expressed in a subgroup of HCC tissues and its expression pattern significantly influenced the levels of drug efflux from HCC cell lines. In MHCC-97L HCC cell line with intrinsic ABCG2 expression, we confirmed the importance of SP cells to the drug efflux-related chemotherapy resistance and found that the SP analysis provided an efficient method to evaluate the functional activity of ABCG2 transporter. In this cell line, we discovered that the SP proportion was modulated by the treatments of Akt signaling inhibitors and serum supplement, which led to the finding that Akt signaling was able to regulate the SP cells' efflux activity via altering the subcellular localization of ABCG2 transporter. We further demonstrated that the Akt signaling inhibition attenuated the doxorubicin efflux from MHCC-97L cells and increased the drug efficacy. Our results indicate the protective role of intrinsic ABCG2 expression in HCC cells and suggest that suppressing Akt signaling could help overcome the drug efflux by ABCG2 transporter.

Lupeol targets liver tumor-initiating cells through phosphatase and tensin homolog modulation

“…In addition, MHCC-LM3 has a high ABCG2 expression. 37 We found that lupeol shrank the tumor volume by induction of apoptosis. Moreover, lupeol did not show signs of toxicity; importantly, the other organs of the mice showed no histological damage or necrosis.…”

Molecular Prognostic Profile of Egyptian HCC Cases Infected with Hepatitis C Virus

“…In the current study ABCG2 genes was up-regulated. Similarly, ABCG2 is expressed in HCC tissues with significant expression pattern that influenced the levels of drug efflux from HCC cell lines (Hu et al, 2008). They verified the protective role of intrinsic ABCG2 expression in HCC cells by modulation of the SP proportion to the Akt signaling inhibitors through altering the subcellular localization of ABCG2 transporter.…”

Tunicamycin Potentiates Cisplatin Anticancer Efficacy through the DPAGT1/Akt/ABCG2 Pathway in Mouse Xenograft Models of Human Hepatocellular Carcinoma

“…In glioma CSCs, the PI3K/Akt pathway has been shown to modulate ABCG2 activity by inhibiting its transport to the plasma membrane (14). We also found that Akt signaling can regulate efflux activity in SP cells by altering the subcellular localization of the ABCG2 transporter (15). The inhibition of Akt signaling can attenuate the efflux of doxorubicin from MHCC-97L hepatocellular carcinoma cells and increase drug efficacy.…”

“…Akt signaling can reportedly control ABCG2 subcellular localization (14,15). Tunicamycin inhibited Akt phosphorylation in several hepatocellular carcinoma cell lines ( Fig.…”