IL-1β is involved in docetaxel chemoresistance by regulating the formation of polyploid giant cancer cells in non-small cell lung cancer

Abstract

AbstractDocetaxel (Doc) is a cornerstone of chemotherapy; however, treatment with Doc often and inevitably leads to drug resistance and the formation of polyploid giant cancer cells (PGCCs). In this study, we investigated the effect of Doc on non-small cell lung cancer to explore the role of PGCCs in drug resistance and the molecular mechanisms that regulate this resistance. We found that Doc induced G2/M cell cycle arrest and cell death in A549 and NCI-H1299 cells. However, many cells remained alive and became PGCCs by decreasing the expression of key regulatory proteins related to the cell cycle and proliferation. Notably, the PGCCs showed typical features of senescence, especially upregulation of p21 and p-histone H2A.X expression. Moreover, the mRNA level of IL-1β in the senescence-associated secretory phenotype was increased significantly with the development of PGCCs. Inhibition of IL-1β reduced the expression of p-histone H2A.X and promoted polyploidy to enhance the proapoptotic effect of Doc. Taken together, our results suggested that IL-1β was involved in the formation of PGCCs and regulated the senescence of PGCCs, which contributed to drug resistance to Doc. Therefore, targeting IL-1β in PGCCs may be a novel approach to overcome drug resistance.