Abstract
Kallikrein-related peptidase 6 (KLK6) is a biomarker of gastric cancer associated with poor prognosis. Mechanisms by which KLK6 could be exploited for chemotherapeutic use are unclear. We evaluated auranofin (AF), a compound with cytotoxic effects, in KLK6-deficient cells, and we investigated whether KLK6 expression induces autophagy and acquisition of drug resistance in gastric cancer. Using cultured human cells and a mouse xenograft model, we investigated how KLK6 affects antitumor-reagent-induced cell death and autophagy. Expression levels of KLK6, p53, and autophagy marker LC3B were determined in gastric cancer tissues. We analyzed the effects of knockdown/overexpression of KLK6, LC3B, and p53 on AF-induced cell death in cancer cells. Increased KLK6 expression in human gastric cancer tissues and cells inhibited AF-induced cell motility due to increased autophagy and p53 levels. p53 dependent induction of KLK6 expression increased autophagy and drug resistance, whereas KLK6 silencing decreased the autophagy level and increased drug sensitivity. During AF-induced cell death, KLK6 and LC3B colocalized to autophagosomes, associated with p53, and were then trafficked to the cytosol. In the xenograft model of gastric cancer, KLK6 expression decreased AF-induced cell death and KLK6-induced autophagy increased AF resistance. Taken together, the data suggest that the induction of autophagic processes through KLK6 expression may increase acquisition of resistance to AF. Our findings may contribute to a new paradigm for tumor therapeutics.
Highlights
Gastric cancer is widespread and among the most lethal of cancers [1]
We examined the levels of KLK1–8 mRNAs compared with GAPDH mRNA in various gastric cancer cell lines using RT-PCR (Figure 1A)
KLK6 expression is increased in many types of tumors and this elevation is related with more aggressive symptoms and poor prognosis [28, 40, 41]; the role of KLK6 in the relationship between autophagy regulation and chemotherapy resistance is currently not well understood
Summary
Gastric cancer is widespread and among the most lethal of cancers [1]. Advancements in biomedical science have led to improved therapies and diagnostics [2]; the problem of drug resistance remains a major obstacle to successful therapeutic approaches against the progression of gastric cancer and indicates a critical need for novel therapeutic approaches [3]. Multiple reports have suggested that autophagy is related to anticancer activity and apoptosis of cancer cells, providing an attractive strategy for improving anticancer therapy [9]. Autophagy is often activated as a survival pathway in chemotherapy-treated tumor cells but becomes a death signal after several treatments. Study of the effects of AF in gastric cancer revealed that AF overcame apoptosis resistance mediated by an anti-cancer drug [25], suggesting that AF may have potential for tumor chemotherapy for various tumors as well. The usability and action of AF in gastric cancer have not yet been demonstrated These findings suggest that repositioning drugs for AF may be a promising approach for cancer treatment. Our results suggest that modulation of KLK6 status to regulate AF-induced autophagic cell death is a potential therapeutic strategy for gastric cancer. We demonstrate that KLK6 overexpression via induction of autophagy may contribute to acquired chemoresistance in gastric cancer
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