PLOD2 increases resistance of gastric cancer cells to 5-fluorouracil by upregulating BCRP and inhibiting apoptosis

Abstract

Background: Gastric cancer (GC) is one of the most common cancers, and it is the third most common cause of cancer-related mortality worldwide. Fluorouracil (5-FU)-based chemotherapy is frequently used for the treatment of advanced GC. However, a substantial proportion of patients eventually experience refractory disease due to drug resistance. PLOD2 was reported to increase invasion and migration in several GC cell lines, but the roles of PLOD2 in chemoresistance are still unclear. The present study aimed to determine whether PLOD2 could confer 5-FU resistance in GC. Methods: The expression of PLOD2 in GC cell lines was assessed by Western blotting. The cells were transfected by lentiviral transduction. The IC50 values were determined by the CCK-8 assay. The migration and invasion abilities of cells were analyzed by the Transwell assay. The proportion of apoptotic cells was assessed by flow cytometry. The protein levels of P-gp (MDR1), MRP1, BCRP (ABCG2), Bax and Bcl2 were analyzed by Western blotting. Furthermore, tumor xenograft models in nude mice were established to test tumor growth and weight. Result: The knockdown of PLOD2 in BGC823 cells significantly decreased the IC50 values of 5-FU. It also contributed to reducing the cell migration and invasion and promoting the apoptosis of GC cells. The opposite results appeared in PLOD2-overexpressing MGC803 GC cells. In vivo experiments showed that the knockdown of PLOD2 increased the growth inhibition of transplanted tumors in nude mice in response to 5-FU. Our mechanistic studies revealed that PLOD2-overexpressing cells appear to be resistant to the therapeutic characteristics of 5-FU in GC cells by upregulating BCRP and that PLOD2 confers resistance to 5-FU-induced apoptosis in GC cells by affecting the expression of Bax and Bcl2. Conclusion: PLOD2 contributed to increasing resistance of gastric cancer cells to 5-fluorouracil by upregulating BCRP and inhibiting apoptosis.

Clinical Prognostic Value of the PLOD Gene Family in Lung Adenocarcinoma

“…In a variety of tumors, fibrous collagen is considered to provide a channel for cancer cell migration and is mainly modified by PLOD2. For example, PLOD2 can increase the invasiveness and migration of gastric cancer (GC) cells and promote their resistance to 5-fluorouracil by upregulating BCRP and inhibiting apoptosis ( Wang et al, 2020 ).…”

A Novel Six-Gene-Based Prognostic Model Predicts Survival and Clinical Risk Score for Gastric Cancer

“…Therefore, PLOD2 may affect cancer progression by modulating collagen cross-linking and maturation ( Kurozumi et al, 2016 ). Wang et al (2020) indicated that PLOD2 can increase the resistance of GC cells to 5-fluorouracil by upregulating BCRP and inhibiting apoptosis. Several studies have indicated that PLOD2 is correlated with poor prognosis of multiple cancers, including sarcoma, GC, lung cancer, renal cell carcinoma, breast cancer, cervical cancer, and bladder cancer ( Miyamoto et al, 2016 ; Du et al, 2017 ; Kiyozumi et al, 2018 ; Chang et al, 2019 ).…”

Case Report: Exome Sequencing Identified a Novel Compound Heterozygous Variation in PLOD2 Causing Bruck Syndrome Type 2

“…Moreover, the genotype-phenotype correlation of BRKS2 is not fully established, owing to the low amount and relatively clustered distribution of constitutional variations in PLOD2 , the vague structural and functional delineation of the N-terminal of LH2 protein as well as the strong phenotypic variability of BRKS2 (Tham et al, 2018 ; Mumm et al, 2020 ). Furthermore, given the commonality of cell signaling pathways between BRKS2 and multiple types of cancers, the in-depth study of corresponding molecules would benefit scientific and clinical understanding in both fields (Guo et al, 2018 ; Wang et al, 2020 ).…”