Aldehyde dehydrogenase 1A1 confers intrinsic and acquired resistance to gemcitabine in human pancreatic adenocarcinoma MIA PaCa-2 cells

Abstract

Gemcitabine (GEM) is front-line standard chemotherapy used for the treatment of pancreatic cancer, but chemoresistance to GEM remains the major obstacle in successful control of this disease. Both expression levels and activity of aldehyde dehydrogenase 1A1 (ALDH1A1) are important features of tumor-initiating and/or cancer stem cell properties in multiple types of humancancers. Since one of the intrinsic properties of cancer stem cells is drug resistance, we tested the relationship between the level and activity of endogenous ALDH1A1 and GEM resistance in the MIA PaCa-2 cell line that contains high expression levels and activity of ALDH1A1. We used small interfering RNAs (siRNAs) to deplete ALDH1A1 and investigate its potential role in conferring GEM resistance. ALDH1A1 knockdown markedly reduced ALDH1A1 expression and activity and inhibited cell proliferation. Moreover, the combination of ALDH1A1-siRNA and GEM significantly decreased cell viability, increased apoptotic cell death and increased accumulation of cells at S-phase compared to controls. Our data also demonstrated that ALDH1A1 expression and activity was significantly higher in GEM-resistant MIA PaCa-2 cell line (MIA PaCa-2/GR), compared to those of parental MIA PaCa-2 cells (MIA PaCa-2/P). In MIA PaCa-2/GR cells, the combination of ALDH1A1-siRNA and GEM also showed significant decrease in cell viability and increase of apoptotic cell death emphasizing the importance of ALDH1A1 in both intrinsic and acquired GEM resistance. This potentially powerful combination treatment of ALDH1A1-siRNA and GEM warrants further investigation as an effective therapeutic regimen to overcome resistance of pancreatic cancer to GEM.

Exosomal lipids induce human pancreatic tumoral MiaPaCa-2 cells resistance through the CXCR-4SDF-1α signaling axis

“…MiaPaCa-2 cells also express pluripotency maintaining transcription factors such as Nanog and Oct4 (data not shown, [25]). Those data confirm the cancer stem-like or cancer initiating statute of the MiaPaCa-2 cell line [13, 14]. Therefore we turn out to cyclopamine (CPA), an antagonist of the Hedgehog self-renewal embryonic pathway which is significantly expressed in cancer promoting cells.…”

“…MiaPaCa-2 cells are also resistant to gemcitabine the gold-standard drug for pancreatic cancer therapies. This intrinsic resistance of MiaPaCa-2 cells to curative drugs has been attributed to their cancer stem-like cells or initiating cells characteristics, notably the aldehyde dehydrogenase (ALDH) overexpression [13, 14]. In pancreatic cancer this ALDH-expressing cell population is particularly sensitive to cyclopamine, an inhibitor of the Hedgehog self-renewal embryonic pathway [15], one of the numerous misregulated signaling pathways in pancreatic cancer [16].…”

Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer

“…ALDH1A1 is also associated with worse PFS and OS in clear cell renal cell carcinoma [45] and breast cancer patients treated with neo-adjuvant chemotherapy [46]. Moreover, ALDH1A1 expression associates with chemoresistance of cultured and xenografted ovarian cancer and pancreatic adenocarcinoma cells [47, 48]. Likewise, gastric cancer cells with high level of ALDH1A1 expression are more resistant to 5-FU and cis -diamminedichloroplatinium than those cells with lower level [49].…”

MicroRNAs expression profile of gefitinib resistant non-small cell lung cancer HCC827 cells

“…The HCC827/P cell line was serially subcultured through incrementally increasing gefitinib concentrations, starting with 0.01 µM for approximately six months. The HCC827/GR cell line retained the capacity for proliferation when returned to medium containing gefitinib (1 µM) [6].…”