Proliferative Suppression by CDK4/6 Inhibition: Complex Function of the Retinoblastoma Pathway in Liver Tissue and Hepatoma Cells

Dayana B. Rivadeneira, Christopher N. Mayhew, Chellappagounder Thangavel, Elena Sotillo, Christopher A. Reed, Xavier Graña, Erik S. Knudsen

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

Background & Aims: Hepatocellular carcinoma is the third leading cause of cancer mortality worldwide; current chemotherapeutic interventions for this disease are largely ineffective. The retinoblastoma tumor suppressor (RB) is functionally inactivated at relatively high frequency in hepatocellular carcinoma and hepatoma cell lines. Here, we analyzed the ability of CDK4/6 inhibition to inhibit hepatocyte proliferation and the effect of RB status on this process. Methods: Hepatoma cell lines and xenograft models harboring RB knockdown and mice harboring liver-specific Rb deletion were used to define the role of RB function in response to CDK4/6 inhibition. Results: Our study shows that CDK4/6-dependent cell cycle progression in hepatoma cells was readily arrested by inhibition of CDK4/6 by PD-0332991 or p16ink4a irrespective of RB status. Interestingly, upon CDK4/6 inhibition, p107 protein stability was dramatically increased as a function of RB loss. This engagement of compensatory mechanisms was critical for cell cycle inhibition in the absence of RB, because both the E1A oncoprotein and overexpression of E2F proteins were capable of overcoming the effect of CDK4/6 inhibition. These findings were recapitulated in xenograft models. Furthermore, to determine how these findings relate to hepatocyte proliferation in vivo, mice were exposed to carbon tetrachloride to induce liver regeneration followed by treatment with PD-0332991. This treatment significantly inhibited hepatocyte proliferation. Strikingly, this facet of PD-0332991 function was retained even in RB-deficient livers. Conclusions: These data show that CDK4/6 inhibition is a potent mediator of cytostasis and that RB loss can be readily compensated for in the context of both hepatoma cell lines and liver tissue.

Original languageEnglish (US)
Pages (from-to)1920-1930.e2
JournalGastroenterology
Volume138
Issue number5
DOIs
StatePublished - May 2010

Keywords

  • CDK4/6 Inhibitor
  • HCC
  • Hepatocellular Carcinoma
  • Retinoblastoma Tumor Suppressor

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Rivadeneira, D. B., Mayhew, C. N., Thangavel, C., Sotillo, E., Reed, C. A., Graña, X., & Knudsen, E. S. (2010). Proliferative Suppression by CDK4/6 Inhibition: Complex Function of the Retinoblastoma Pathway in Liver Tissue and Hepatoma Cells. Gastroenterology, 138(5), 1920-1930.e2. https://doi.org/10.1053/j.gastro.2010.01.007