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Transforming growth factor‐beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth
Author(s) -
Senturk Serif,
Mumcuoglu Mine,
GursoyYuzugullu Ozge,
Cingoz Burcu,
Akcali Kamil Can,
Ozturk Mehmet
Publication year - 2010
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.23769
Subject(s) - senescence , cancer research , biology , transforming growth factor , transforming growth factor beta , cell culture , endocrinology , microbiology and biotechnology , genetics
Senescence induction could be used as an effective treatment for hepatocellular carcinoma (HCC). However, major senescence inducers (p53 and p16 Ink4a ) are frequently inactivated in these cancers. We tested whether transforming growth factor‐β (TGF‐β) could serve as a potential senescence inducer in HCC. First, we screened for HCC cell lines with intact TGF‐β signaling that leads to small mothers against decapentaplegic (Smad)‐targeted gene activation. Five cell lines met this condition, and all of them displayed a strong senescence response to TGF‐β1 (1‐5 ng/mL) treatment. Upon treatment, c‐myc was down‐regulated, p21 Cip1 and p15 Ink4b were up‐regulated, and cells were arrested at G 1 . The expression of p16 Ink4a was not induced, and the senescence response was independent of p53 status. A short exposure of less than 1 minute was sufficient for a robust senescence response. Forced expression of p21 Cip1 and p15 Ink4b recapitulated TGF‐β1 effects. Senescence response was associated with reduced nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) induction and intracellular reactive oxygen species (ROS) accumulation. The treatment of cells with the ROS scavenger N ‐acetyl‐ L ‐cysteine, or silencing of the NOX4 gene, rescued p21 Cip1 and p15 Ink4b accumulation as well as the growth arrest in response to TGF‐β. Human HCC tumors raised in immunodeficient mice also displayed TGF‐β1–induced senescence. More importantly, peritumoral injection of TGF‐β1 (2 ng) at 4‐day intervals reduced tumor growth by more than 75%. In contrast, the deletion of TGF‐β receptor 2 abolished in vitro senescence response and greatly accelerated in vivo tumor growth. Conclusion: TGF‐β induces p53‐independent and p16 Ink4a ‐independent, but Nox4‐dependent, p21 Cip1 ‐dependent, p15 Ink4b ‐dependent, and ROS‐dependent senescence arrest in well‐differentiated HCC cells. Moreover, TGF‐β–induced senescence in vivo is associated with a strong antitumor response against HCC. H EPATOLOGY 2010