Antitumor effect of SIRT1 inhibition in human HCC tumor models in vitro and in vivo
Menée in vitro et in vivo, cette étude met en évidence l'intérêt d'une stratégie visant à inhiber la sirtuine SIRT1 pour le traitement d'un carcinome hépatocellulaire
Sirtuins (SIRT1-7) are a highly conserved family of NAD+ dependent enzymes that control the activity of histone and non-histone regulatory proteins. SIRT1 is known to promote longevity and to suppress the initiation of some cancers. Nevertheless, SIRT1 is reported to function as a tumor suppressor as well as an oncogenic protein. Our data show that compared to normal liver or surrounding tumor tissue, SIRT1 is strongly over-expressed in human hepatocellular carcinoma (HCC). Additionally, human HCC cell lines (Hep3B, HepG2, HuH7, HLE, HLF, HepKK1, skHep1) were screened for the expression of the sirtuin family members and only SIRT1 was consistently overexpressed compared to normal hepatocytes. To determine its effect on HCC growth, SIRT1 activity was inhibited either with lentiviruses expressing shRNAs or with the small molecule inhibitor, cambinol. Knockdown or inhibition of SIRT1 activity had a cytostatic effect, characterized by an altered morphology, impaired proliferation and an increased expression of differentiation markers and cellular senescence. In an orthotopic xenograft model, knockdown of SIRT1 resulted in 50% fewer animals developing tumors and cambinol treatment resulted in an overall lower tumor burden. Taken together, our data demonstrate that inhibition of SIRT1 in HCC cells impairs their proliferation in vitro and tumor formation in vivo. These data suggest that SIRT1 expression positively influences the growth of HCC and support further studies aimed to block its activity alone or in combination as a novel treatment strategy.
http://mct.aacrjournals.org/content/early/2013/01/19/1535-7163.MCT-12-0700.abstract