Premium
CD133 + liver cancer stem cells from methionine adenosyl transferase 1A–deficient mice demonstrate resistance to transforming growth factor (TGF)‐β–induced apoptosis
Author(s) -
Ding Wei,
Mouzaki Marialena,
You Hanning,
Laird Joshua C.,
Mato Jose,
Lu Shelly C.,
Rountree C. Bart
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22743
Subject(s) - biology , cancer stem cell , stem cell , microbiology and biotechnology , cancer research , population , clone (java method) , biochemistry , medicine , dna , environmental health
Methionine adenosyltransferase (MAT) is an essential enzyme required for S ‐adenosylmethionine biosynthesis. Hepatic MAT activity falls during chronic liver injury, and mice lacking Mat1a develop spontaneous hepatocellular carcinoma by 18 months. We have previously demonstrated that CD133 + CD45 − oval cells isolated from 16‐month‐old Mat1a −/− mice represent a liver cancer stem cell population. The transforming growth factor β (TGF‐β) pathway constitutes a central signaling network in proliferation, apoptosis, and tumorigenesis. In this study, we tested the response of tumorigenic liver stem cells to TGF‐β. CD133 + CD45 − oval cells were isolated from premalignant 16‐month‐old Mat1a −/− mice by flow cytometry and expanded as five clone lines derived from a single cell. All clone lines demonstrated expression of both hepatocyte and cholangiocyte markers and maintained a small population (0.5% to 2%) of CD133 + cells in vitro, and three of five clone lines produced tumors. Although TGF‐β1 inhibited cell growth equally in CD133 − and CD133 + cells from each clone line, the CD133 + population demonstrated significant resistance to TGF‐β–induced apoptosis compared with CD133 − cells. Furthermore, CD133 + cells demonstrated a substantial increase in mitogen‐activated protein kinase (MAPK) pathway activation, as demonstrated by phosphorylated extracellular signal‐regulated kinase levels before and after TGF‐β stimulation. MAPK inhibition using mitogen‐activated protein kinase kinase 1 (MEK1) inhibitor PD98059 led to a significant increase in TGF‐β–induced apoptosis in CD133 + cells. Conversely, a constitutively active form of MEK1 blocked the apoptotic effects of TGF‐β in CD133 − cells. Conclusion: CD133 + liver cancer stem cells exhibit relative resistance to TGF‐β–induced apoptosis. One mechanism of resistance to TGF‐β–induced apoptosis in CD133 + cancer stem cells is an activated mitogen‐activated protein kinase/extracellular signal‐regulated kinase pathway. (H EPATOLOGY 2009.)