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Apicidin Sensitizes Pancreatic Cancer Cells to Gemcitabine by Epigenetically Regulating MUC4 Expression

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Apicidin Sensitizes Pancreatic Cancer Cells to Gemcitabine by Epigenetically Regulating MUC4 Expression ANTICANCER RESEARCH 34: 5269-5276 (2014) Apicidin Sensitizes Pancreatic Cancer Cells to Gemcitabine by Epigenetically Regulating MUC4 Expression DANIEL ANSARI1, CARLOS UREY1, KATARZYNA SAID HILMERSSON1, MONIKA P. BAUDEN1, FREDRIK EK2, ROGER OLSSON2 and ROLAND ANDERSSON1 1Department of Surgery, Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden; 2Chemical Biology & Therapeutics, Department of Experimental Medical Science, Lund University, Lund, Sweden Abstract. Background/Aim: Mucin 4 (MUC4) has been also as the reference agent in most clinical trials. However, linked to resistance to gemcitabine in pancreatic cancer cells. the beneficial effect of gemcitabine on overall patient The aim of the present study was to assess whether epigenetic survival is limited due to high resistance of pancreatic cancer control of MUC4 expression can sensitize pancreatic cancer cells to the drug (6). cells to gemcitabine treatment. Materials and Methods: A 76- Mucins are high molecular-weight glycoproteins that are member combined epigenetics and phosphatase small- important in pancreatic tumorigenesis (7). Studies on mucin molecule inhibitor library was screened for anti-proliferative 4 (MUC4) have revealed that its expression is silenced in activity against the MUC4+ gemcitabine-resistant pancreatic normal pancreatic ducts (8, 9). MUC4 is up-regulated in the cancer cell line Capan-1, followed by high-content screening majority of pancreatic carcinomas, and is associated with of protein expression. Results: Apicidin, a histone deacetylase invasive proliferation of tumors and a poor outcome (10, 11). inhibitor, showed the greatest anti-proliferative activity with a On the basis of experimental studies, MUC4 has been lethal dose 50 (LD50) value of 5.17 μM. Apicidin significantly proposed as a factor that imparts resistance to pancreatic reduced the expression of MUC4 and its transcription factor cancer cells to gemcitabine (6, 12, 13). hepatocyte nuclear factor 4α. Combined treatment with a sub- The molecular mechanisms responsible for mucin gene therapeutic concentration of apicidin and gemcitabine activation in pancreatic cancer are slowly becoming known. synergistically inhibited growth of Capan-1 cells. Conclusion: Recent data indicate that mucin genes may be epigenetically- Apicidin appears to be a novel anti-proliferative agent against regulated in pancreatic cancer (14). An investigation of the pancreatic cancer cells that may reverse chemoresistance by detailed epigenetic mechanisms of MUC4 expression has epigenetically regulating MUC4 expression. shown that regulation of MUC4 expression involves both DNA methylation and histone H3 modification mediated by Pancreatic cancer ranks as the fourth leading cause of DNA methyltransferases and histone deacetylases (HDACs) cancer-related death (1). Effective treatment strategies are in pancreatic cancer cells (8). lacking. If no substantial breakthroughs occur within the next The aim of the present study was to assess whether years, pancreatic cancer is to become the second leading epigenetic control of MUC4 expression can sensitize cause of cancer-related death, preceded only by lung cancer pancreatic cancer cells to gemcitabine treatment. (2). Standard therapy for advanced pancreatic cancer consists of combinations of gemcitabine, a nucleoside analog (3). Materials and Methods Although there has been some advancement in the Cell culture. Human pancreatic cancer cell lines Capan-1 (MUC4+) development of other cytotoxic agents against pancreatic and Panc-1 (MUC4−) (ATCC®, Manassas, VA, USA) were maintained cancer (4, 5), gemcitabine is routinely used in the clinic and as a monolayer in Iscove’s modified Dulbecco’s medium (Gibco, Life Technologies, Grand Island, NY, USA) or in Dulbecco’s modified Eagle’s medium (Gibco) supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin (100 U/ml), respectively. The cells Correspondence to: Roland Andersson, Department of Surgery, were grown in T-75 culture flasks (Sarstedt, Nümbrecht, Germany) Clinical Sciences Lund, Skåne University Hospital, Lund, Sweden. kept at 37˚C in 5% CO2 in an incubator. Culture media were changed Tel: +46 46172359, e-mail: [email protected] twice a week and the cells passaged before reaching confluence. Before experiments, the cells were washed with Dulbecco’s phosphate- Key Words: Apicidin, capan-1, epigenetics, histone deacetylase buffered saline without Ca2+ or Mg2+ (DPBS) (Gibco), detached using inhibitor, HNF4α, MUC4, pancreatic cancer, phosphatase inhibitor, TrypLe 10× (Gibco) for 5-15 min, harvested and pelleted at 300 ×g small-molecule inhibitor library, targeted treatment. for 3 min. After pellet dissociation by repeated gentle pipetting, cell 0250-7005/2014 $2.00+.40 5269 ANTICANCER RESEARCH 34: 5269-5276 (2014) Table I. The combined epigenetics and small-molecule phosphatase inhibitor library. Name Plate description Compound description 2,4-pyridinedicarboxylic acid Epigenetics library Histone demethylase inhibitor 5-aza-2'-deoxycytidine (Decitabine) Epigenetics library DNA methyltransferase inhibitor 9,10-Phenanthrenequinone Phosphatase inhibitor iibrary CD45 tyrosine phosphatase AGK2 Epigenetics library SIRT2 inhibitor Alendronate Phosphatase inhibitor iibrary Tyrosine phosphatases Alexidine·2HCl Phosphatase inhibitor iibrary PTPMT1 Aminoresveratrol sulfate Epigenetics library SIRT1 activator Anacardic acid Epigenetics library HAT inhibitor Apicidin Epigenetics library HDAC inhibitor B2 Epigenetics library SIRT2 inhibitor B4-Rhodanine Phosphatase inhibitor iibrary PRL3 Benzylphosphonic acid Phosphatase inhibitor iibrary Tyrosine phosphatases BIX-01294·3HCl Epigenetics library Histone methyl transferase inhibitor BML-210 Epigenetics library HDAC inhibitor BML-260 Phosphatase inhibitor iibrary JSP-1 BML-266 Epigenetics library SIRT2 inhibitor BML-267 Phosphatase inhibitor iibrary PTP1B BML-267 Ester Phosphatase inhibitor iibrary PTP1B (cell permeable) BML-278 Epigenetics library SIRT1 actvator BML-281 Epigenetics library HDAC-6 inhibitor BN-82002 Phosphatase inhibitor iibrary CDC25 Butyrolactone 3 Epigenetics library HAT inhibitor BVT-948 Phosphatase inhibitor iibrary Tyrosine phosphatases Cantharidic acid Phosphatase inhibitor iibrary PP1 and PP2A Cantharidin Phosphatase inhibitor iibrary PP1 and PP2A CI-994 Epigenetics library HDAC inhibitor CinnGel Phosphatase inhibitor iibrary PTP1B CTPB Epigenetics library HAT activator Cyclosporin A Phosphatase inhibitor iibrary Calcineurin (PP2B) Cypermethrin Phosphatase inhibitor iibrary Calcineurin (PP2B) Deltamethrin Phosphatase inhibitor iibrary Calcineurin (PP2B) Endothall Phosphatase inhibitor iibrary PP2A EX-527 Epigenetics library SIRT1 inhibitor Fenvalerate Phosphatase inhibitor iibrary Calcineurin (PP2B) Fluoro-SAHA Epigenetics library HDAC inhibitor Garcinol Epigenetics library HAT inhibitor Gossypol Phosphatase inhibitor iibrary Calcineurin (PP2B) Isonicotinamide Epigenetics library Nicotinamide antagonist ITSA-1 Epigenetics library Inhibitor of TSA activity L-p-Bromotetramisole oxalate Phosphatase inhibitor iibrary Tyrosine phosphatases Levamisole HCl Phosphatase inhibitor iibrary Mammalian alkaline phosphatase M-344 Epigenetics library HDAC inhibitor MC-1293 Epigenetics library HDAC inhibitor NCH-51 Epigenetics library HDAC inhibitor Nicotinamide Epigenetics library SIRT inhibitor NSC-3852 Epigenetics library HDAC inhibitor NSC-663284 Phosphatase inhibitor iibrary CDC25 NSC-95397 Phosphatase inhibitor iibrary CDC25 Nullscript Epigenetics library Scriptaid Neg control OBA Phosphatase inhibitor iibrary Tyrosine phosphatases OBA Ester Phosphatase inhibitor iibrary Tyrosine phosphatases (cell permeable) Oxamflatin Epigenetics library HDAC inhibitor Pentamidine Phosphatase inhibitor iibrary PRL1 Phenylbutyrate·Na Epigenetics library HDAC inhibitor Piceatannol Epigenetics library SIRT activator Resveratrol Epigenetics library SIRT1 activator RK-682 Phosphatase inhibitor iibrary Tyrosine phosphatases RWJ-60475 Phosphatase inhibitor iibrary CD45 tyrosine phosphatase Table I. continued 5270 Ansari et al: Apicidin Epigenetically Regulates MUC4 in Pancreatic Cancer Cells Table I. continued Name Plate description Compound description RWJ-60475 (AM)3 Phosphatase inhibitor iibrary CD45 tyrosine phosphatase (cell permeable) Salermide Epigenetics library SIRT inhibitor Sanguinarine chloride Phosphatase inhibitor iibrary PP2C Scriptaid Epigenetics library HDAC inhibitor Shikonin Phosphatase inhibitor iibrary Sirtinol Epigenetics library SIRT inhibitor Splitomicin Epigenetics library SIRT2 inhibitor Suberoyl bis-hydroxamic acid Epigenetics library HDAC inhibitor Suramin·6Na Epigenetics library SIRT1 inhibitor Tetramisole HCl Phosphatase inhibitor iibrary Mammalian alkaline phosphatase Tranylcypromine hemisulfate Epigenetics library Lysine demethylase inhibitor Triacetylresveratrol Epigenetics library SIRT1 activator Trichostatin A Epigenetics library HDAC inhibitor Tyrphostin 8 Phosphatase inhibitor iibrary Calcineurin (PP2B) Valproic acid Epigenetics library HDAC inhibitor Valproic acid hydroxamate Epigenetics library HDAC inhibitor Vorinostat (SAHA) Epigenetics library HDAC inhibitor Zebularine Epigenetics library DNA methyltransferase inhibitor CD45: Cluster of differentiation 45; CDC25: cell division cycle 25; HAT: histone acetyltransferase; HDAC: histone deacetylase; JSP-1: JNK stimulatory phosphatase 1; SIRT: sirtuin; PP1: protein phosphatase 1; PP2A: protein phosphatase 2A; PP2B: protein phosphatase 2B; PP2C: protein
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