Abstract
Lung cancer is the leading cause of cancer death worldwide and the therapeutic strategies include surgery, chemotherapy and radiation therapy. Non-small cell lung cancers (NSCLCs) account for around 85% of cases of lung cancers. Pemetrexed is an antifolate agent that is currently used as the second line chemotherapy drug in the treatment of advanced NSCLC patients with a response rate of 20–40%. The search for any combination therapy to improve the efficacy of pemetrexed is required. The existence of cancer stem cells (CSCs) is considered as the main reason for drug resistance of cancers. In this study, we first found that pemetrexed-resistant NSCLC cells derived from A549 cells displayed higher CSC activity in comparison to the parental cells. The expression of CSC related proteins, such as BMI1 or CD44, and the epithelial–mesenchymal transition (EMT) signature was elevated in pemetrexed-resistant NSCLC cells. We next discovered that the overexpression of BMI1 in A549 cells caused the pemetrexed resistance and inhibition of BMI1 by a small molecule inhibitor, PTC-209, or transducing of BMI1-specific shRNAs suppressed cell growth and the expression of thymidylate synthase (TS) in pemetrexed-resistant A549 cells. We further identified that BMI1 positively regulated SP1 expression and treatment of mithramycin A, a SP1 inhibitor, inhibited cell proliferation, as well as TS expression, of pemetrexed-resistant A549 cells. Furthermore, overexpression of BMI1 in A549 cells also caused the activation of EMT in and the enhancement of CSC activity. Finally, we demonstrated that pretreatment of PTC-209 in mice bearing pemetrexed-resistant A549 tumors sensitized them to pemetrexed treatment and the expression of Ki-67, BMI1, and SP1 expression in tumor tissues was observed to be reduced. In conclusion, BMI1 expression level mediates pemetrexed sensitivity of NSCLC cells and the inhibition of BMI1 will be an effective strategy in NSCLC patients when pemetrexed resistance has developed.
Highlights
Lung cancer is the leading cause of cancer-related death in the world
We demonstrated that BMI1 could induce Specificity protein 1 (SP1) expression and lead to the upregulation of thymidylate synthase (TS, gene name as TYMS), a key enzyme for vice versa
Have established the pemetrexed-resistant cells compared from A549 the cells,cancer stem cells (CSCs)
Summary
Non-small-cell lung cancer (NSCLC) represents 87% of patients with lung cancer, and is clinically divided into two major subtypes: adenocarcinoma and squamous cell carcinoma [1]. Most lung cancer patients present with advanced-stage disease and the current 5-year survival for lung cancer is only 18% [2]. Even in patients with early-stage resectable or locally advanced disease after standard treatment, the lung cancer recurrence rate is up to 90% [3]. Over the past two decades, multiple treatments are under clinical practice for NSCLC patients such as surgery, chemotherapy, targeted therapy, immunotherapy and radiotherapy. Systemic chemotherapy is still the principal treatment for NSCLC, especially as palliative care for late-stage patients [4]. Platinum-based chemotherapy has been used for standard first-line regimen for advanced
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