BMI1-Mediated Pemetrexed Resistance in Non-Small Cell Lung Cancer Cells Is Associated with Increased SP1 Activation and Cancer Stemness

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.

The Potential Mechanism of HDAC1-Catalyzed Histone Crotonylation of Caspase-1 in Nonsmall Cell Lung Cancer

“…Alimta (also known as pemetrexed) is a multitargeted antifolate agent that has been proved to exhibit e ective single-agent activity in patients with NSCLC [6][7][8][9] and is widely studied as the synergetic agent for NSCLC therapy in various clinical studies [10][11][12][13]. However, the resistance to pemetrexed is frequently occurred in multiple cancers and severely a ects the NSCLC therapy [14][15][16].…”

Combination of PKCδ Inhibition with Conventional TKI Treatment to Target CML Models

“…It regulates oncogenic phenotypes and promotes CSCs and therapy resistance in cancer cells [ 31 , 32 ]. Pharmacological BMI1 inhibitors such as PTC-209 [ 33 , 34 , 35 ] and PTC-296 [ 36 ] have shown promising results in different types of cancers, but associated treatments have not yet been offered. Our results indicate that the decrease in BMI1 expression triggered by PKCδ inhibition could be an important feature of PKCδ inhibitors and explain their effectiveness.…”

L-Type Amino Acid Transporter 1 Regulates Cancer Stemness and the Expression of Programmed Cell Death 1 Ligand 1 in Lung Cancer Cells

“…We had previously established pemetrexed-resistant NSCLC cells from A549 cells by continued treatment with 400 nM of pemetrexed; these cells are called A400 cells [17]. The CSC activity of A400 cells was found to have increased when compared to parental A549 cells using tumorsphere cultivation (Figure 1A).…”

“…The mRNA expression of several cancer stemness genes including BMI1, Sox2, Oct4, and c-Myc, was upregulated in A400 cells (Figure 1B). We previously found that the sensitivity of H1299 cells to pemetrexed was between A549 cells and A400 cells [17]. Thus, the H1299 cells were included to investigate the relationship between LAT1 and pemetrexed sensitivity.…”