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: 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.

Background: Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive cancer characterized by high mortality and morbidity. The five-year survival rate is less than 5%, due to a lack of therapeutic agents and biomarkers for early detection. Therefore, it is critical to identify and develop new therapeutic targets for PDAC therapy. Here, we highlight the evidence for an interactive mechanism between CD74 activation in cancer cells and the release of pro-inflammatory cytokines by cancer associated fibroblasts (CAFs) in the tumor microenvironment (TME) in PDAC. Methods: By suppressing the expression of CD74 in pancreatic cancer cells, we found that CD74 triggered TRAF6-mediated activation of the NF-kB pathway, leading to the expression and secretion of various inflammatory factors into the TME as confirmed by ELISA secretion assay. Furthermore, we found that these secretory factors bind to the receptors on CAFs to induce release of pro-inflammatory cytokines by the TME. Expressions of pro-inflammatory cytokines in CAFs were upregulated as verified by western blot. Results: Here, we highlight the evidence for an interactive mechanism between CD74 activation in cancer cells and the release of pro-inflammatory cytokines by cancer associated fibroblasts (CAFs) in the tumor microenvironment (TME) in PDAC. Conclusions: Taken together, our findings are by far the first to present a supportive role of CD74 in constituting a more pro-inflammatory condition in the TME in PDAC.