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

Xiaohui Wang; Jiaojiao Guo; Meng Dai; Tengqi Wang; Tingting Yang; Xuejun Xiao; Qi Tang; Lingli Zhang; Lizhou Jia

doi:10.7150/jca.41828

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

J Cancer. 2020 Mar 13;11(12):3467-3475. doi: 10.7150/jca.41828. eCollection 2020.

Authors

Xiaohui Wang^{1

2}, Jiaojiao Guo³, Meng Dai^{1

4}, Tengqi Wang^{1

4}, Tingting Yang³, Xuejun Xiao⁵, Qi Tang³, Lingli Zhang⁶, Lizhou Jia^{1

4}

Affiliations

¹ Cancer Center, Bayannur Hospital, Bayannur, Inner Mongolia, PR China.
² Department of Pharmacy, Inner Mongolia Medical University, Hohhot, Inner Mongolia, PR China.
³ Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
⁴ Bayannur Clinical Medical College, Inner Mongolia Medical University, Bayannur, Inner Mongolia, PR China.
⁵ Department of Pharmacology, Xinjiang Medical University, Wulumuqi, Xinjiang, PR China.
⁶ Department of Ophthalmology, Inner Mongolia Autonomous Region People's Hospital, Hohhot, PR China.

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.

Keywords: 5-Fluorouracil; BCRP (ABCG2); Gastric cancer; PLOD2; drug resistance.