Tectochrysin Attenuates the Chemoresistance of Hepatocellular Carcinoma Cells to Sorafenib by Inhibiting the PI3K/AKT Signaling Pathway and ABCG2 Expression.

A flavonoid compound known as tectochrysin (TEC), which is extracted from Alpinia Oxyphylla Miq, possesses anti-cancer properties across a range of cancer types. This study aims to investigate its role in reversing sorafenib (SR) resistance in hepatocellular carcinoma (HCC) and the underlying mechanism. SR-resistant HCC cells (Huh7 SR and HCCLM3 SR) were generated through long-term induction of parental cells with escalating doses of SR. Cell viability was evaluated by CCK-8 assays. Cell proliferation was assessed by colony formation assays. Flow cytometry analysis was used to analyze cell apoptosis and cell cycle. Transwell and wound healing assays were applied to detect cell invasion and migration, respectively. Immunofluorescence staining was used to detect ABCG2 expression and p-AKT nuclear translocation. Cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assay were performed to validate the binding of TEC to PI3K and ABCG2 protein. HCC cell-derived xenograft models were used to confirm the anti-cancer effects of TEC in vivo. Western blot analysis was employed to detect the levels of proteins related to apoptosis, epithelial-mesenchymal transition (EMT), and the PI3K/AKT/ABCG2 pathway in cells and tissues. TEC significantly augmented the sensitivity of SR-resistant HCC cell lines to SR, synergistically inhibiting cell proliferation and colony formation. Combination treatment with TEC and SR potently induced G1/S cell cycle arrest and promoted apoptosis, accompanied by regulation of Bcl-2, Bax, C-PARP, C-caspase-3. Furthermore, TEC combined with SR effectively suppressed cell migration, invasion, and EMT, upregulating E-cadherin while downregulating N-cadherin and Vimentin. Mechanistically, TEC combined with SR exerted inhibitory effects on the PI3K/AKT/ABCG2 signaling. Evidence for this includes reduced expression of ABCG2, p-AKT, and p-PI3K, compromised ABCG2 expression, and attenuated nuclear translocation of p-AKT. In vivo, TEC and SR synergistically inhibited the growth of xenograft tumors derived from SR-resistant cells and reduced the expression of Ki67, ABCG2, and PI3K/AKT pathway proteins. Our study illustrates that TEC alleviates SR-associated chemoresistance in HCC cells by restraining activation of the PI3K/AKT signaling and inhibiting ABCG2 expression. This finding identifies TEC as a potential candidate to tackle SR resistance in HCC.