Beste Yurdacan Yasar, Elmasnur Yilmaz, Yasemin Erac
These findings suggest that SOCE is associated with early adaptive responses to sorafenib in Huh7 cells, and that its pharmacological inhibition may enhance sorafenib-induced antitumor effects. Given the reliance on a single cell line and a non-selective pharmacological inhibitor, these findings should be considered hypothesis-generating, and further validation using additional HCC models and genetic approaches is warranted.
PURPOSE: Sorafenib remains a systemic treatment option for advanced hepatocellular carcinoma (HCC), but its clinical efficacy is limited by rapid development of adaptive cellular responses that promote cell survival and phenotypic plasticity. Store-operated calcium entry (SOCE) is a key regulator of intracellular calcium signaling and has been implicated in proliferation, apoptosis, migration, and epithelial-mesenchymal plasticity in cancer. This study investigated the association between SOCE and early adaptive responses to sorafenib in Huh7 HCC cells.
METHODS: Huh7 cells were treated with sorafenib, the SOCE inhibitor SKF-96365, or their combination. Functional effects were evaluated using real-time proliferation assays, intracellular calcium measurements, apoptosis analysis, and wound-healing assays. Findings were complemented by integrated bioinformatic analyses of TCGA-LIHC and related HCC datasets.
RESULTS: Sorafenib treatment significantly enhanced calcium influx following endoplasmic reticulum calcium depletion, consistent with activation of SOCE as part of an adaptive response. Pharmacological inhibition of SOCE markedly attenuated this calcium influx and suppressed cell proliferation. Combined treatment enhanced sorafenib-induced apoptosis and reduced wound closure, accompanied by decreased expression of mesenchymal markers and increased E-cadherin levels, consistent with a shift toward a more epithelial phenotype. Integrated bioinformatic analyses revealed an association between TRPC6-related signaling and epithelial-mesenchymal plasticity, as well as subtype-specific expression patterns linked to aggressive tumour behavior in human HCC datasets.
CONCLUSION: These findings suggest that SOCE is associated with early adaptive responses to sorafenib in Huh7 cells, and that its pharmacological inhibition may enhance sorafenib-induced antitumor effects. Given the reliance on a single cell line and a non-selective pharmacological inhibitor, these findings should be considered hypothesis-generating, and further validation using additional HCC models and genetic approaches is warranted.