The Role of Store-Operated Calcium Entry in Sorafenib Responses in Hepatocellular Carcinoma
Project no. 23075 · Status: Kapanmış (Yayın bekleniyor) · 2021
Summary
<p>Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide, with most cases diagnosed at advanced stages where effective treatment options are limited. Sorafenib (SOR), a multi-kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR) and the Raf-MEK-ERK signaling pathways, is used as a first-line therapy for HCC. Despite the survival advantage observed in HCC patients, the therapeutic efficacy of SOR remains restricted. This limitation is due to an incomplete understanding of the signaling pathways contributing to HCC progression and the molecular therapeutic targets affected by SOR.</p><p>Calcium plays a crucial role in cellular functions such as secretion, neural excitation, muscle contraction, transcription, cell division, and apoptosis. In cancer cells, calcium homeostasis is reprogrammed, and alterations in calcium signaling have been shown to contribute to carcinogenesis in several cancer types. In HCC, the primary calcium regulator, Store-Operated Calcium Entry (SOCE), is associated with increased proliferation rates, migration, and invasion processes. Moreover, studies in various cancer types indicate that targeting SOCE can inhibit proliferation, migration, and invasion in HCC under in vitro and in vivo conditions. However, the effect of SOCE on SOR responses in HCC remains unknown.</p><p>This proposed project aims to evaluate the potential effects of a SOCE activator (Thapsigargin) and a SOCE inhibitor (2-APB) on SOR’s expected responses—namely, reduced proliferation and increased apoptosis levels—in Huh7 cells. Additionally, the effects of SOR on SOCE in Huh7 cells will be investigated through 1) proliferation rate, 2) intracellular calcium concentration, 3) apoptosis levels, and 4) mRNA and protein expression levels of SOCE-related components TRPC1, TRPC6, STIM1, and Orai1. This project thus seeks to identify, for the first time, the therapeutic potential of SOCE activators/inhibitors in HCC treatment. Most of the experiments will be conducted using the infrastructure of the Department of Pharmacology and the Pharmaceutical Sciences Research Laboratory.</p>