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SP1 Mediates MRP1 Upregulation and Multi-Drug Resistance in Human Lung Cancer Cells
40 Pages Posted: 30 Jul 2019
More...Abstract
Background: Chemotherapy is currently one of the most common/important treatments for cancers; however the occurrence of multidrug resistance (MDR) impedes the successful application of chemotherapeutic agents. The active efflux of anti-cancer drugs through multi-drug resistance protein 1 (MRP1) remains the dominant mechanism of MDR. However, mechanisms underlying the MRP1 upregulation during tumorigenesis and chemotherapy remain elusive.
Methods: MRP1 expression, the efflux probability and viability were measured to evaluate MDR of human lung cancer A549/DDP and H1299 cells. Pharmacological treatment, shRNA-based konckdown and rescue were used to assess the function of JNK (c-Jun N-terminal kinase) and Sp1 (stimulatory phosphatase 1). Chromatin immunoprecipitation and dual-luciferase reporter assay were used to test the direct binding and activation of MRP1 promotor by Sp1.
Findings: Pharmacological analysis and JNK knockdown revealed the direct modulation of MRP1 expression and MDR by by the JNK signaling pathway. Furthermore, the transcript factor Sp1 downstream of JNK showed close association with MRP1 expression and MDR. Chromatin immunoprecipitation and luciferase assays revealed the direct binding and activation of MRP1 promoter by Sp1, while Sp1 knockdown decreased MRP1 expression and reversed MDR. Importantly, the MRP1 upregulation and MDR mediated by JNK activation were substantially abolished by Sp1 knockdown in both A549/DDP and H1299 cells.
Interpretation: This work demonstrates that Sp1 is a critical transcription factor for MRP1 downstream of JNK and plays a key role in MRP1 upregulation and MDR during tumorigenesis and chemotherapy. Targeting Sp1 expression/activation sheds new light on the clinical chemotherapy treatments of cancers.
Funding Statement: This work was supported by the National Natural Science Foundation of China (31400708 and 31670843), the Natural Science Foundation of Heilongjiang Province, China (C200624, C201241, and C201453), the Shaanxi Natural Science Funds for Distinguished Young Scholars of China (2019JC-07), the Key Research and Development Program of Shaanxi Province, China (2017SF-113), and the Fundamental Research Funds for the Central Universities (2017qngz10).
Declaration of Interests: The authors declare no competing financial interests.
Ethics Approval Statement: Not required.
Keywords: MRP1; multi-drug resistance; JNK; Sp1; chemoresistance; transcription factor
Suggested Citation: Suggested Citation