Abstract
During chemotherapy, drug resistance caused by autophagy remains a major challenge to successful treatment of cancer patients. The purpose of this study is to show that ulinastatin (UTI), a trypsin inhibitor, could reduce the resistance of liver cancer cells to chemotherapeutic agent epirubicin (EPI). We achieved this conclusion by analyzing the effect of EPI alone or UTI plus EPI on SMMC-7721 and MHCC-LM3 liver cancer cells. We also generated an EPI-resistant liver cancer cell line (MHCC-LM3er cells), and found that UTI could sensitize the LM3er cells to EPI. Autophagy usually functions to protect cancer cells during chemotherapy. Our study showed that UTI inhibited the autophagy induced by EPI in liver cancer cells, which promoted apoptosis, and therefore, reduced the resistance of the cancer cells to EPI. Further studies showed that the UTI-mediated inhibition on autophagy was achieved by inhibiting transcriptional factor nuclear factor-κB (NF-κB) signaling pathway. To verify our results in vivo, we injected MHCC-LM3 liver cancer cells or EPI-resistant LM3er cells into mice, and found that EPI could only effectively inhibit the growth of tumor in MHCC-LM3 cell-injected mice, but not in LM3er cell-injected mice. However, when UTI was also administered, the growth of tumor was inhibited in the MHCC-LM3er cell-injected mice as well. Our results suggest that UTI may be used in combination with anti-cancer drugs, such as EPI, to improve the outcome of cancer therapy.
Highlights
Autophagy is an essential cellular process responsible for the degradation of damaged and dysfunctional cellular organelles and protein aggregates
EPI has been reported to induce autophagy in breast cancer cells and causes drug resistance [15]. To verity if it has the similar effect in liver cancer cells, we treated SMMC-7721 cells with EPI at various concentrations to determine the range that EPI could effectively induce autophagy [15, 18]
We treated SMMC-7721 and MHCC-LM3 cells with EPI or EPI+UTI, the increase of LC3-II and decrease of SQSTM1 were significantly inhibited by EPI+UTI treatment, suggesting that the EPI-induced autophagy was inhibited by the addition of UTI (Fig 1D)
Summary
Autophagy is an essential cellular process responsible for the degradation of damaged and dysfunctional cellular organelles and protein aggregates. This is a process conserved among yeast, plant, and animal cells and is important for providing sources of energy in response to nutrient stress and at critical times in development [1]. Developing and established tumors have high metabolic demands due to increased proliferation and high apoptotic thresholds In this case, autophagy serves as a survival mechanism in many tumor cells, allowing them to escape apoptotic death in response to metabolic crisis. It has been suggested that by combining with agents that disrupt autophagy, the effectiveness of anti-cancer drug may be enhanced [5]
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