Background: Pancreatic cancer has the fourth lowest survival rate in worldwide because it is difficult to detect it in the early stage. Gemcitabine is mainly utilized as a primary treatment to cure the disease. However, it has been proved that gemcitabine has a poor outcome to cure due to its chemoresistance. Therefore, it is necessary to discover a new therapeutic target to overcome the gemcitabine resistance. Methods/Results: Here, we found that SLC38A5 is highly overexpressed in gemcitabine-resistant pancreatic patients than normal cancer patients. In this study, we found that inhibition of SLC38A5 attenuated gemcitabine resistance in vitro and in vivo. Blockade of SLC38A5 significantly lowered cell proliferation as confirmed by WST assay and glutamine uptake via glutamine assay kit. In addition, inhibition of SLC38A5 induces ferroptosis by inducing lipid ROS through GSH-mediated GPX4 expression and mTOR-SREBP1 signaling. Conclusions: Altogether, our results demonstrate that SLC38A5 could be a novel therapeutic target to overcome gemcitabine resistance for PDAC therapy.

Background: Pancreatobiliary cancer surgery is a very complex and extensive surgery. so patients feel high psychological stress due to fear of returning to daily life after surgery and as well as various physical symptoms. This study aims to identify the degree of distress experienced by pancreatobiliary cancer patients during the recovery period after surgery and to analyze the factors that affect it. Methods: This study retrospectively investigated a total of 141 patients who underwent surgery for pancreaticobiliary cancer between December 1, 2019 and September 30, 2021. Distress was measured using Distress Thermomenter (DT) and Problem List (PL) tools developed by NCCN. Descriptive statistics and logistic regression analysis were used to analyze data. Results: A total of 141 patients were enrolled, and the average distress score was 6.31 (± 2.49). The moderate-severe distress group (DT ≥ 4) was 119 (84.4%), and the mild distress group (DT < 4) was 22 (15.6%). The list of problems that caused the patient's distress included pain (62.4%), sleep disturbance (51.1%), worry (48.2%), fear/digestion (39.0%), and difficulty eating (36.9%) appeared in order. Looking at the relationship between the distress groups according to the demographic and treatment-related characteristics of the subjects, gender (χ 2 = 4.48, p = 0.034) and occupational status (χ 2 = 8.75, p = 0.003) were statistically significant between the two groups. The relationship between the distress groups according to the list of distress problems of the subject was dyspepsia (χ 2 = 9.81, p = 0.002), difficulty eating (χ 2 = 3.92, p = 0.048), and difficulty with behavior (χ 2 = 4.19 p = 0.041), there were more subjects in the moderate-severe distress group than in the mild distress group. In order to identify the factors affecting the patient's distress, a binary logistic regression analysis was conducted by including gender, occupational status, and list of distress problems that were statistically significant. The factors contributing to patients distress were not statistically significant in multivariate analysis. Conclusions: Pancreaticobiliary cancer patients experience severe distress after surgery.

Background: Pancreatic Ductal Adenocarcinoma (PDAC) is known as one of the fatal cancers that have a high mortality worldwide. Gemcitabine is one of well-known drugs to treat pancreatic cancer patients. However, as a limit of mono-therapy, gemcitabine tends to cause drug resistance in pancreatic cancer. Therefore, it is significant to discover novel therapeutic agents for gemcitabine resistance therapy. The present study represents the first study evaluating the relationship between gemcitabine resistant cancer cells and tumor micro-environment in PDAC. Methods: Here, we found that regulation of SLC6A14 disrupts glutamine production from surrounding tumor microenvironment to weaken drug resistance in PDAC cells. In addition, blockade of SLC6A14 dysregulated cell proliferation as determined by WST assay and induced high levels of ROS as determined by DCF-DA staining via FACS and evidenced by down-regulation of NRF2 and GPX4 expression. Moreover, inhibition of SLC6A14 showed anti-tumor effect as proved by inactivated mTOR and NF-κB expression. Further, our findings showed that suppression of SLC6A14 effectively decreases tumor size and growth in gemcitabine-resistant pancreatic cancer in vivo. Results: Altogether, our results indicate that SLC6A14 is involved in oncogenic effect in PDAC by inducing glutamine production from tumor micro-environment. Conclusions: SLC6A14 could be a novel potential candidate to improve weakness of gemcitabine monotherapy in drug resistance in PDAC.