ABCA8-mediated efflux of taurocholic acid contributes to gemcitabine insensitivity in human pancreatic cancer via the S1PR2-ERK pathway

Abstract

The development of resistance to anticancer drugs is believed to cause chemotherapy failure in pancreatic cancer (PC). The efflux of anticancer drugs mediated by ATP-binding cassette (ABC) transporters is a widely accepted mechanism for chemoresistance, but for ABCA subfamily members, which are characterized by their ability to transport lipids and cholesterol, its role in chemoresistance remains unknown. Here we found that the expression of ABCA8, a member of ABCA subfamily transporters, was significantly increased in human PC cells after gemcitabine (GEM) treatment, as well as in established GEM-resistant (Gem-R) PC cells. Importantly, ABCA8 knockdown reversed the chemoresistance phenotype of Gem-R cells, whereas ABCA8 overexpression significantly decreased the sensitivity of human PC cells to GEM, both in vitro and in vivo, demonstrating an important role of ABCA8 in regulating chemosensitivity. Moreover, our results showed that treatment with taurocholic acid (TCA), an endogenous substrate of ABCA8, also induced GEM insensitivity in PC cells. We further demonstrated that ABCA8 mediates the efflux of TCA out of PC cells, and that extracellular TCA activates extracellular signal-regulated kinase (ERK) signaling via the sphingosine 1-phosphate receptor 2 (S1PR2), which is responsible for ABCA8-induced GEM ineffectiveness. Together, these findings reveal a novel TCA-related mechanism of ABCA subfamily transporter-mediated chemoresistance that goes beyond the role of a drug pump and suggest ABCA8 or the TCA-S1RP2-ERK pathway as potential targets for improving the effectiveness of and overcoming the resistance to chemotherapy in PC.

Strategies to gain novel Alzheimer’s disease diagnostics and therapeutics using modulators of ABCA transporters

“… 231 The sterol derivatives estradiol-β-glucuronide, estrone sulfate, and taurocholic acid ( Figure 1 ), but also the physiological substrate leukotriene C4 (LTC 4 ), the natural compound ochratoxin A, as well as the chemical p -amino hippuric acid were discovered as (potential) ABCA8 substrates. 10 , 221 , 222 Specifically the ABCA8-mediated taurocholate export from various human pancreatic cancer cell lines was suggested as the major mechanism behind gemcitabine resistance in these cells, 221 which was corroborated in HEK293 cells stably expressing ABCA8. 10 …”

“…However, several potential intrinsic substrates of ABCA8 have been identified. 10 , 221 , 222 Furthermore, a significant number of ABCA transporter modulators have been identified on this target. 222 Hence, ABCA8 represents a good model system for the development of potential therapeutics targeting other ABCA transporters taking the scarce knowledge on this transporter subclass into account.…”

“…The most genuine interactors of ABCA transporters are intrinsic substrates of these transporters. These include cholesterol ( Figure 1 ) and other sterol derivatives, 10 , 221 , 222 , 228 but also phospholipids ( Figure 1 ), sphingolipids 228 , 229 and retinoids ( e.g., all-trans -retinal; Figure 1 ). 133 - 138 In addition, certain intrinsic molecules were demonstrated to interact with ABCA transporters, in particular with ABCA1 230 and ABCA8.…”

“… 133 - 138 In addition, certain intrinsic molecules were demonstrated to interact with ABCA transporters, in particular with ABCA1 230 and ABCA8. 10 , 221 , 222 α-tocopherol (vitamin E) was demonstrated to be transported by ABCA, 230 and to interfere with ABCA1 regulation. 231 The sterol derivatives estradiol-β-glucuronide, estrone sulfate, and taurocholic acid ( Figure 1 ), but also the physiological substrate leukotriene C4 (LTC 4 ), the natural compound ochratoxin A, as well as the chemical p -amino hippuric acid were discovered as (potential) ABCA8 substrates.…”

“…ABCA8 mRNA and ABCA8 protein content were induced by gemcitabine in PANC-1 and CFPAC-1 human pancreatic cancer cells. 221 In rat liver, an induction of Abca8 was demonstrated via microarray analysis of cDNA when the rats were exposed to polyethyleneglycol-block-polylactide nanoparticles. 433 …”