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Transport-mediated Oxaliplatin Resistance Associated With Endogenous Overexpression of MRP2 in Caco-2 and PANC-1 Cells

Biswas, R; Bugde, P; He, J; Merien, F; Lu, J; Liu, DX; Myint, K; Liu, J; McKeage, M; Li, Y
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http://hdl.handle.net/10292/12990
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Abstract
Our recent publications showed that multidrug resistance protein 2 (MRP2, encoded by the ABCC2 gene) conferred oxaliplatin resistance in human liver cancer HepG2 cells. However, the contribution of MRP2 to oxaliplatin resistance remains unclear in colorectal and pancreatic cancer lines. We investigated the effects of silencing MRP2 by siRNA on oxaliplatin accumulation and sensitivity in human colorectal cancer Caco-2 cells and pancreatic cancer PANC-1 cells. We characterized the effects of oxaliplatin on MRP2 ATPase activities using membrane vesicles. Over-expression of MRP2 (endogenously in Caco-2 and PANC-1 cells) was associated with decreased oxaliplatin accumulation and cytotoxicity, but those deficits were reversed by inhibition of MRP2 with myricetin or siRNA knockdown. Silencing MRP2 by siRNA increased oxaliplatin-induced apoptotic rate in Caco-2 and PANC-1 cells. Oxaliplatin stimulated MRP2 ATPase activity with a concentration needed to reach 50% of the maximal stimulation (EC50) value of 8.3 ± 0.7 µM and Hill slope 2.7. In conclusion, oxaliplatin is a substrate of MRP2 with possibly two binding sites, and silencing MRP2 increased oxaliplatin accumulation and cytotoxicity in two widely available gastrointestinal tumour lines (PANC-1 and Caco-2).
Keywords
Gastrointestinal cancer; Multidrug resistance protein 2 (MRP2); Oxaliplatin
Date
2019
Source
Cancers, 11(9), 1330. MDPI AG. Retrieved from http://dx.doi.org/10.3390/cancers11091330
Item Type
Journal Article
Publisher
MDPI AG
DOI
10.3390/cancers11091330
Publisher's Version
https://www.mdpi.com/2072-6694/11/9/1330
Rights Statement
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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