High pemetrexed sensitivity of docetaxel-resistant A549 cells is mediated by TP53 status and downregulated thymidylate synthase

Abstract

The chemoresistance of non-small cell lung cancer (NSCLC) that occurs in docetaxel (DOC) chemotherapy substantially decreases the survival of patients. To overcome DOC-induced chemoresistance, we established DOC-selected A549 lung cancer sublines (A549/D16 and A549/D32) and revealed that both sublines were cross-resistant to vincristine (VCR) and doxorubicin (DXR). Notably, both sublines were more sensitive to pemetrexed (PEM) than parental cells according to MTT and clonogenic assays. The expression levels of thymidylate synthase (TS) and γ-glutamyl hydrolase (GGH) were downregulated in DOC-resistant sublines. When exogenous TS was overexpressed in A549/D16 cells, PEM sensitivity was significantly decreased, however it was not decreased by overexpression of exogenous GGH. PEM treatment induced more apoptotic sub-G1 cells in both DOC-resistant sublines and in the in vivo PEM sensitivities of A549/D16 cells. These findings were further confirmed by a xenografted tumor model. To unmask the mediator of TS downregulation, we investigated human lung cancer cell lines that have various TP53 statuses using DOC treatment. The level of TS protein was significantly decreased in wild-type TP53-containing cells with DOC treatment; TS expression levels were not affected in mutant-TP53 and TP53-null cells under the same conditions. Furthermore, when the expression of TP53 was inhibited in A549 cells, the expression level of TS was increased. Our data indicated that DOC activated wild-type TP53 and suppressed TS expression under continuous DOC exposure. Therefore, the expression of TS remained at low levels in DOC-resistant A549 cancer cells. Our data revealed that for lung cancer with DOC resistance and wild-type TP53 status, the administration of PEM as a second-line agent to overcome DOC-resistance may benefit patients.

Increase in resistance to anticancer drugs involves occludin in spheroid culture model of lung adenocarcinoma A549 cells

“…1A ). Similarly, cross resistance to anticancer drugs are reported in docetaxel-resistant 23 and gemcitabine-resistant A549 cells 24 . The detailed mechanism of acquisition of chemoresistance has not been fully understood.…”

Study on the Differentially Expressed Genes and Signaling Pathways in Systemic Lupus Erythematosus Using Integrated Bioinformatics Method

“…As a transcription factor, p53 induces the expression of downstream genes such as p21, BAX and GADD4 and plays an important role in cell apoptosis, cycle change, DNA repair, cell metabolism and autophagy [25] . Related studies have found that p53 gene polymorphism is associated with systemic lupus erythematosus susceptibility in Asian populations [26][27] . It has also been found that p53 induces the production of related proteins by binding to speci c DNA sequences, thereby inhibiting the expression of DNA methyltransferase gene, thereby affecting DNA methylation level [28] .…”

MTAP-deficiency could predict better treatment response in advanced lung adenocarcinoma patients initially treated with pemetrexed-platinum chemotherapy and bevacizumab

“…www.nature.com/scientificreports www.nature.com/scientificreports/ for pemetrexed. Another study also revealed that the sensitivity of pemetrexed depends on the level of TS 18 . In A549 lung cancer cell line with downregulated TS level induced by docetaxel-resistance, pemetrexed sensitivity was increased compared to those parental cells, whereas it was decreased when exogenous TS was overexpressed in the docetaxel-resistant A549 cell line.…”