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

Zhiyu Chen, Veena Sangwan, Sulagna Banerjee, Tiffany Mackenzie, Vikas Dudeja, Xiaowu Li, Huaizhi Wang, Selwyn M. Vickers, Ashok Saluja

Research output: Contribution to journalArticle

44 Citations (Scopus)

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.

Original languageEnglish (US)
Article number105
JournalMolecular Cancer
Volume12
Issue number1
DOIs
StatePublished - Sep 11 2013
Externally publishedYes

Fingerprint

Myeloid Leukemia
Myeloid Cells
Pancreatic Neoplasms
Cell Death
Neoplasms
Cell Survival
Cell Line
Apoptosis Regulatory Proteins
Survival
Diterpenes
3' Untranslated Regions
Luciferases
Heterografts
Small Interfering RNA
Up-Regulation
Therapeutics
Down-Regulation
triptolide
Water

Keywords

  • Cell death
  • Mcl-1
  • miR 204
  • Pancreatic cancer
  • Triptolide

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

Cite this

MiR-204 mediated loss of Myeloid cell leukemia-1 results in pancreatic cancer cell death. / Chen, Zhiyu; Sangwan, Veena; Banerjee, Sulagna; Mackenzie, Tiffany; Dudeja, Vikas; Li, Xiaowu; Wang, Huaizhi; Vickers, Selwyn M.; Saluja, Ashok.

In: Molecular Cancer, Vol. 12, No. 1, 105, 11.09.2013.

Research output: Contribution to journalArticle

Chen, Zhiyu ; Sangwan, Veena ; Banerjee, Sulagna ; Mackenzie, Tiffany ; Dudeja, Vikas ; Li, Xiaowu ; Wang, Huaizhi ; Vickers, Selwyn M. ; Saluja, Ashok. / MiR-204 mediated loss of Myeloid cell leukemia-1 results in pancreatic cancer cell death. In: Molecular Cancer. 2013 ; Vol. 12, No. 1.
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