Abstract
BackgroundApatinib, a novel vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, has been approved for the treatment of metastatic gastric cancer and other tumors. Apatinib exerts antiproliferative and proapoptotic effects in different kinds of cancer cells. However, the molecular mechanisms by which apatinib effective against esophageal squamous cell carcinoma (ESCC) have only been partially researched and whether it has a sensitizing effect on paclitaxel remains unclear.Materials and methodsThe effects of apatinib or paclitaxel on endoplasmic reticulum (ER) stress, autophagy, apoptosis and proliferation of ESCC cell lines were evaluated. Western blot and immunohistochemistry analyses were performed to detect the expression of related genes. The weight and volume of xenograft tumors in mice were measured.ResultsIn the current study, we elucidated the antiproliferative and ER-stress-mediated autophagy-inducing effects of apatinib on ECA-109 and KYSE-150 esophageal squamous cancer cells and identified the underlying mechanisms of its action. We demonstrated that apatinib not only inhibited the proliferation and induced the apoptosis of ESCC cells, but also activated ER stress and triggered protective autophagy. Moreover, inhibiting autophagy by chloroquine (CQ) enhanced the apatinib-induced apoptosis of ESCC cells through the IRE-1α–AKT–mTOR pathway. In addition, we showed, for the first time, the paclitaxel combined with apatinib and CQ exhibited the best antitumor effect on ESCC both in vivo and in vitro via the IRE-1α–AKT–mTOR pathway.ConclusionsOur data showed that apatinib induced ER stress, autophagy and apoptosis in ESCC. Inhibiting autophagy by CQ enhanced apatinib-induced apoptosis. The combination of apatinib and CQ sensitized ESCC cells to paclitaxel to induce apoptosis through the IRE-1α–AKT–mTOR signaling pathway, thus providing the basis for its use in innovative anticancer therapeutic strategies.Graphic abstract
Highlights
esophageal squamous cell carcinoma (ESCC) is the type of esophageal cancer predominant in East Asia, especially in China, where it accounts for more than 90% of cases [1, 2]
We demonstrated that apatinib inhibited the proliferation and induced the apoptosis of ESCC cells, and activated endoplasmic reticulum (ER) stress and triggered protective autophagy
Our data showed that apatinib induced ER stress, autophagy and apoptosis in ESCC
Summary
ESCC is the type of esophageal cancer predominant in East Asia, especially in China, where it accounts for more than 90% of cases [1, 2]. Despite advances in diagnosis and therapy in recent decades, the 5-year survival rate remains low at an estimated 15–20% [7]. The combination of chemotherapy and targeted therapy has provided opportunities for improving outcomes in recent years. As a novel VEGFR-2 tyrosine kinase inhibitor [10, 11], is the second antiangiogenic drug that has been approved for the therapy of advanced metastatic gastric cancer [12]. A novel vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, has been approved for the treatment of metastatic gastric cancer and other tumors. The molecular mechanisms by which apatinib effec‐ tive against esophageal squamous cell carcinoma (ESCC) have only been partially researched and whether it has a sensitizing effect on paclitaxel remains unclear
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