Abstract
Lung cancer management remains a challenge due to its asymptomatic and late presentation when it is metastatic. The clinical response to the first-line platinum-based chemotherapy in patients with advanced lung cancer is disappointing due to the development of chemoresistance. Chemoresistance is a complex phenomenon. Mechanistic research using experimental models has yielded limited clinical results to help increase understanding for overcoming resistance. While the role of lung CSCs in conferring multidrug resistance has been postulated, experimental evidence remains associative and lacks in depth mechanistic inquisition. In the present study, using mouse and human lung adenocarcinoma cell lines and their respective paired CSC derivative cell lines that we generated, we identified cancer stem cell component of lung adenocarcinoma as the source that confers multidrug resistance phenotype. Mechanistically, Gstp1 confers cisplatin resistance in mouse and human lung CSC models, both in vitro and in vivo. Further, transcriptional activation of Gstp1 expression by MEK/ERK signaling underlies cisplatin resistance in lung CSC cells. Moreover, we show that GSTP1 expression is a poor diagnostic and prognostic marker for human lung adenocarcinoma, thus is of high clinical relevance. Taken together, we have provided mechanistic understanding of the lung CSC in mediating chemoresistance.
Highlights
Lung cancer is the most common cause of cancer-related deaths in the world [1]
To discern the potential genes that mediate multidrug resistance in the LLC-SD cells, we examined the expression of known multidrug resistance genes, including Gstp1, Abca2, Mrp1, Abcg2 and Mdr1, by RT-qPCR
Mechanistic research of the involvement of commonly studied multidrug resistant genes using human lung adenocarcinoma cell lines has yielded limited clinical results to help increase the understanding for overcoming resistance
Summary
The high mortality rate (51–99%) of lung adenocarcinoma is due to it being asymptomatic, it having late presentation when it is metastatic and becoming resistant to anti-cancer therapies [2]. In spite of the development of new therapeutic strategies, the outcome of patients with metastatic lung cancer has barely improved over the past few decades, and the overall 5-year survival rate remains very low (10–15%) [3, 4]. Lung adenocarcinoma is the most common histological type of lung cancer, comprising ∼60% of non-small cell lung cancers (NSCLC) [5]. Platinum-based chemotherapy represents the standard first-line treatment for patients with advanced NSCLC, therapeutic outcome is disappointing due to the development of chemo-resistance, relapse, and distant metastases [6, 7]. Mechanistic understanding of the involvement of commonly studied multidrug resistant genes using human lung adenocarcinoma cell lines has yielded limited clinical success in overcoming chemo-resistance far
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