Twist promotes invasion and cisplatin resistance in pancreatic cancer cells through growth differentiation factor 15.

ABSTRACT

Pancreatic cancer (PC) is an aggressive and devastating disease with a poor prognosis. Cisplatin, a commonly used chemotherapeutic agent for solid tumors, is effective as a single agent or in combination with other drugs for the treatment of PC. Previous studies have suggested that Twist and growth differentiation factor 15 (GDF15) are involved in the progression of PC. However, the role of Twist and GDF15 in PC remains to be elucidated. In the present study, the individual effect of and interaction between Twist and GDF15 in PC cell invasion and chemoresistance to cisplatin was examined. Twist and/or GDF15 were stably overexpressed or knocked down in ASPC­1 and BXPC­3 human PC cells. Overexpression of Twist in the two cell lines markedly increased GDF15 expression, cell invasion, matrix metalloproteinase­2 expression/activity and the half maximal inhibitory concentration (IC50) values of cisplatin, which was eradicated by GDF15 knockdown or the selective p38 mitogen­activated protein kinase (MAPK) inhibitor SB203580 (10 µM). By contrast, Twist knockdown significantly decreased GDF15 expression, cell invasion, matrix metalloproteinase­2 expression/activity and the IC50 values of cisplatin, which was completely reversed by overexpression of GDF15. In addition, while overexpression and knockdown of Twist increased and decreased p38 MAPK activity, respectively, GDF15 demonstrated no significant effect on p38 MAPK activity in PC cells. In conclusion, the present study, for the first time, to the best of our knowledge, demonstrated that Twist promotes PC cell invasion and cisplatin chemoresistance through inducing GDF15 expression via a p38 MAPK­dependent mechanism. The present study provides new insights into the molecular mechanisms underlying PC progression and chemoresistance.