MGLL Coordinates YWHAZ to Mediate Gemcitabine Resistance in Pancreatic Cancer via IL6/PI3K/AKT Signaling Pathway

Abstract

Background: The frequency of neoplastic disorders, pancreatic ductal adenocarcinoma (PDAC), is increasing annually. PDAC is an aggressive cancer and can be partly managed with systemic chemotherapy, as it is usually diagnosed at advanced stages. Unfortunately, only 23.8% PDAC patients are clinically sensitive to gemcitabine (GEM) treatment. Therefore, this study aimed to understand the etiology and pathobiology of chemoresistance in PDAC, deciphering the molecular mechanisms underlying PDAC progression. Methods: The expression levels of two important genes were investigated in the clinical tissues samples of gemcitabine-sensitive and gemcitabine-resistant PDAC patients. Furthermore, lentivirus was used to knock down and overexpress target genes, and RNA sequencing was utilized to further investigate the downstream regulators. Additionally, plate cloning, flow cytometry, and in vivo tumorigenicity were used to demonstrate the involvement of these key genes in gemcitabine resistance in PDAC. Eventually, the downstream regulators of gemcitabine resistance of PDAC was assessed using western blot (WB) and enzyme-linked immunosorbent assay (ELISA), respectively, aiming to evaluate the impacts of phosphatidylinositol 3-kinase and protein kinase B (PI3K/AKT) pathway-related proteins and Interleukin 6 (IL6) inflammatory factor. Results: The expressions of monoacylglycerol lipase (MGLL) and Tryptophan 5-Monooxygenase Activation Protein Zeta (YWHAZ) were higher in gemcitabine-resistant PDAC patients than in gemcitabine-sensitive PDAC patients (p < 0.05). In vitro experiments revealed that both overexpression and silencing of these genes altered the capacity to establish gemcitabine resistance (p < 0.05). RNA sequencing results indicated that these two genes combinedly regulate the expression of IL6 and demonstrated that they regulate drug resistance by activating the PI3K/AKT signaling pathway (p < 0.05). Moreover, in vivo experiments validated the involvement of MGLL and YWHAZ in improving gemcitabine resistance in pancreatic cancer (p < 0.05). Conclusions: This study demonstrates that MGLL and YWHAZ co-regulate the resistance to gemcitabine via the IL6/PI3K/AKT axis in PDAC. Therefore, MGLL/YWHAZ is a promising therapeutic target for the treatment of PDAC.