TY - JOUR
T1 - The metabolic regulator PGC- 1α links anti- cancer cytotoxic chemotherapy to reactivation of hepatitis B virus
AU - Mouler Rechtman, M.
AU - Burdelova, E. O.
AU - Bar-Yishay, I.
AU - Ben-Yehoyada, M.
AU - Fishman, S.
AU - Halpern, Z.
AU - Shlomai, A.
PY - 2013/1
Y1 - 2013/1
N2 - Patients with chronic hepatitis B virus (HBV) infection are at an increased risk for a severe and a potentially fatal viral reactivation following anti- cancer therapy. The molecular mechanism for this induction of HBV expression is still unclear. Here, we show that treating hepatoma cell line expressing HBV with various anti- cancer cytotoxic agents results in a significant up- regulation of HBV expression. This HBV induction is at the transcriptional level and is time dependent. Interestingly, treating hepatoma cells with anti- cancer cytotoxic agents results in a robust induction of peroxisome proliferator- activated receptor- gamma coactivator- 1α (PGC- 1α), a metabolic and energy regulator that is normally induced in the liver under starvation conditions and that has been previously shown to strongly coactivate HBV transcription. Most importantly, HBV up- regulation following anti- cancer therapy depends on PGC- 1α induction, because PGC- 1α knock- down abolishes HBV induction. Finally, pretreatment of HBV- expressing cells with the antioxidant agent N- acetylcysteine attenuates the induction of both PGC- 1α and HBV in response to anti- cancer treatment, suggesting that chemotherapy- associated PGC- 1α induction is mediated by cellular oxidative stress that ultimately leads to HBV up- regulation. We conclude that cytotoxic anti- cancer chemotherapy has a direct and an immune system- independent effect on HBV gene expression, which is mediated by PGC- 1α. Our results attribute to this metabolic regulator an unexpected role in linking anti- cancer treatment to HBV reactivation and make PGC- 1α a potential target for future anti- HBV therapy, especially under conditions in which it is robustly induced, such as following anti- cancer treatment.
AB - Patients with chronic hepatitis B virus (HBV) infection are at an increased risk for a severe and a potentially fatal viral reactivation following anti- cancer therapy. The molecular mechanism for this induction of HBV expression is still unclear. Here, we show that treating hepatoma cell line expressing HBV with various anti- cancer cytotoxic agents results in a significant up- regulation of HBV expression. This HBV induction is at the transcriptional level and is time dependent. Interestingly, treating hepatoma cells with anti- cancer cytotoxic agents results in a robust induction of peroxisome proliferator- activated receptor- gamma coactivator- 1α (PGC- 1α), a metabolic and energy regulator that is normally induced in the liver under starvation conditions and that has been previously shown to strongly coactivate HBV transcription. Most importantly, HBV up- regulation following anti- cancer therapy depends on PGC- 1α induction, because PGC- 1α knock- down abolishes HBV induction. Finally, pretreatment of HBV- expressing cells with the antioxidant agent N- acetylcysteine attenuates the induction of both PGC- 1α and HBV in response to anti- cancer treatment, suggesting that chemotherapy- associated PGC- 1α induction is mediated by cellular oxidative stress that ultimately leads to HBV up- regulation. We conclude that cytotoxic anti- cancer chemotherapy has a direct and an immune system- independent effect on HBV gene expression, which is mediated by PGC- 1α. Our results attribute to this metabolic regulator an unexpected role in linking anti- cancer treatment to HBV reactivation and make PGC- 1α a potential target for future anti- HBV therapy, especially under conditions in which it is robustly induced, such as following anti- cancer treatment.
KW - Hepatitis B virus
KW - chemotherapy
KW - peroxisome proliferator- activated receptor- gamma coactivator- 1α
KW - reactivation
UR - http://www.scopus.com/inward/record.url?scp=84871023873&partnerID=8YFLogxK
U2 - 10.1111/j.1365-2893.2012.01622.x
DO - 10.1111/j.1365-2893.2012.01622.x
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C2 - 23231082
AN - SCOPUS:84871023873
SN - 1352-0504
VL - 20
SP - 34
EP - 41
JO - Journal of Viral Hepatitis
JF - Journal of Viral Hepatitis
IS - 1
ER -