Promotes Cancer Cell Drug Resistance Research Articles

Osteopontin promotes cancer cell drug resistance, invasion, and lactate production and is associated with poor outcome of patients with advanced non-small-cell lung cancer.

BackgroundOsteopontin (OPN), a member of the small integrin binding ligand N-linked glycoprotein family, has been analyzed in numerous types of human malignancy.PurposeThe present study detected the expression levels of OPN and evaluated its role in tumor progression in patients with non-small cell lung cancer (NSCLC).Patients and methodsOPN expression levels were detected using immunohistochemistry in 101 NSCLC tumors. The mRNA and protein levels have significant difference between advanced NSCLC and stage I/II NSCLC. The drug resistance, invasive ability and lactate production of NSCLC cancer cell lines (A549 and SK-MES-1) were detected in cancer cells with the disturbance of OPN.ResultsImmunostaining indicated that OPN was primarily expressed in the cytoplasm of NSCLC cells. Moreover, OPN correlates with NSCLC clinical traits. The results demonstrated that OPN expression levels significantly correlated with cancer differentiation, distant metastasis and the efficacy of platinum-based treatment. Notably, the results identified OPN expression levels as a potential factor for predicting the response of cells to first-line platinum-based chemotherapy using multivariate analysis, as well as predicting cancer differentiation and distant metastasis. Additionally, the abrogation of OPN levels reduced lactate production in NSCLC cells and occurred along side with the downregulation of lactate dehydrogenase A (LDHA).ConclusionThe results of the current study suggest that OPN may be able to predict poor prognosis and cisplatin resistance in patients.

Abstract 5462: Extracellular ATP promotes cancer cell drug resistance to tyrosine kinase inhibitors by competing for the ATP-binding site of tyrosine kinase

Abstract ATP plays important roles in cellular processes in cancer cells, which are a heterogeneous population in tumors regarding their genetic background and oxygen and energy supplies. The fact that cancer cells undergo rapid proliferation suggests that they must possess mechanisms, which may not be present in normal cells, to meet their high energy needs. Studies by others revealed that extracellular ATP levels of various cancer types are 10^3 to 10^4 times higher than those in their corresponding normal tissues (1). We recently reported that extracellular ATP can be taken up directly by cancer cells by macropinocytosis (2). Based on these results, we hypothesized that the internalized extracellular ATP not only promotes cancer cell growth and survival, but also drug resistance. In this study, human lung cancer A549 and breast cancer MCF7 cells were used as cell models to determine the effects of extracellular ATP on drug resistance to tyrosine kinase inhibitors (TKIs) in cancer cells. Cancer cell viability and intracellular ATP measurement results showed that extracellular ATP substantially increased intracellular ATP levels and promoted cancer cell drug resistance to TKIs. Viability of TKI treated cancer cells was significantly increased in the presence of extracellular ATP, compared to cancer cells with TKI treatment alone. Administration of macropinocytosis inhibitors significantly reduced the drug resistance induced by extracellular ATP, suggesting that extracellular ATP promoted drug resistance by contributing to the intracellular ATP pool. Protein and protein phosphorylation analyses results suggested that the increased intracellular ATP reversed the inhibition of TKIs by competing with the inhibitor for the ATP-binding site of platelet-derived growth factor receptor (PDGFR) and enhancing Akt and MAPK signaling pathways. These findings identify, for the first time, new biological functions of extracellular ATP in tumors and may lead to novel anti-cancer strategies combating drug resistance in cancers. 1. Pellegatti P, et al. PLoS ONE 2008;3:e2599. 2. Qian Y, et al. Cancer Lett 2014;351:242-51. Citation Format: Xuan Wang, Yanrong Qian, Yunsheng Li, Xiaozhuo Chen. Extracellular ATP promotes cancer cell drug resistance to tyrosine kinase inhibitors by competing for the ATP-binding site of tyrosine kinase. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5462. doi:10.1158/1538-7445.AM2015-5462