miR-204 mediated loss of Myeloid cell leukemia-1 results in pancreatic cancer cell death.

Abstract

BACKGROUND:

Pancreatic cancer is one of the most lethal human malignancies, with an all-stage 5-year survival of <5%, mainly due to lack of effective available therapies. Cancer cell survival is dependent upon up-regulation of the pro-survival response, mediated by anti-apoptotic proteins such as Mcl-1.

RESULTS:

Here we show that over-expression of Mcl-1 in pancreatic patient tumor samples is linked to advancement of the disease. We have previously shown that triptolide, a diterpene triepoxide, is effective both in vitro and in vivo, in killing pancreatic cancer cells. Decrease of Mcl-1 levels, either by siRNA or by treatment with triptolide results in cell death. Using pancreatic cancer cell lines, we have shown that miR-204, a putative regulator of Mcl-1, is repressed in cancer cell lines compared to normal cells. Over-expression of miR-204, either by a miR-204 mimic, or by triptolide treatment results in a decrease in Mcl-1 levels, and a subsequent decrease in cell viability. Using luciferase reporter assays, we confirmed the ability of miR-204 to down-regulate Mcl-1 by directly binding to the Mcl-1 3' UTR. Using human xenograft samples treated with Minnelide, a water soluble variant of triptolide, we have shown that miR-204 is up-regulated and Mcl-1 is down-regulated in treated vs. control tumors.

CONCLUSION:

Triptolide mediated miR-204 increase causes pancreatic cancer cell death via loss of Mcl-1.

• Authors: Zhiyu Chen, Veena Sangwan, Sulagna Banerjee, Tiffany Mackenzie, Vikas Dudeja, Xiaowu Li, Huaizhi Wang, Selwyn M Vickers, Ashok K Saluja
• Journal: Molecular cancer (Mol Cancer) Vol. 12 Issue 1 Pg. 105 (Sep 11 2013) ISSN: 1476-4598 [Electronic] England
• PMID: 24025188 (Publication Type: Journal Article)

Chemical References

• 3' Untranslated Regions
• Antineoplastic Agents
• Diterpenes
• Epoxy Compounds
• MCL1 protein, human
• MIRN204 microRNA, human
• MicroRNAs
• Myeloid Cell Leukemia Sequence 1 Protein
• Organophosphates
• Phenanthrenes
• triptolide
• 14-O-phosphonooxymethyltriptolide disodium salt

Topics

• 3' Untranslated Regions
• Animals
• Antineoplastic Agents (pharmacology)
• Base Sequence
• Binding Sites
• Cell Death
• Cell Line, Tumor
• Diterpenes (pharmacology)
• Epithelium (metabolism)
• Epoxy Compounds (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Liver Neoplasms (drug therapy, metabolism, secondary)
• Mice
• Mice, SCID
• MicroRNAs (physiology)
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Organophosphates (pharmacology)
• Pancreatic Ducts (metabolism, pathology)
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Phenanthrenes (pharmacology)
• RNA Interference
• Up-Regulation
• Xenograft Model Antitumor Assays