Poster Presentation 29th Lorne Cancer Conference 2017

Metabolism and Ribosome Biogenesis in Oncogene-Induced Senescence (#298)

HAORAN ZHU 1 , Rick Pearson 1 , JIAN KANG 1
  1. Peter MacCallum Cancer Centre, MELBOURNE, VICTORIA, Australia

Cellular senescence was firstly described by Hayflick and Moorhead in 1961 as a phenomenon by which human fibroblasts in culture have a limited replicative capacity and eventually cease to divide and become immortal. A type of senescence called premature senescence can be trigger by various stresses, such as oncogene activation or inactivation of tumor suppressor genes. DNA damage response has been causally implicated in the establishment of premature senescence. Therefore, premature senescence is considered as a protective barrier against tumorigenesis, and this senescence brake must be overcome for malignant transformation. Understanding how Oncogene-Induced Senescence (OIS) is maintained in non-transformed cells and how it is subverted in cancer cells is a fundamental question in cancer biology.

Despite growth arrest, senescent cells remain metabolically active. Such metabolic reprogramming is now considered to be critical for senescence induction and maintenance. An overall shift in glucose metabolism in OIS cells towards mitochondrial metabolism is the stark contrast to a shift of glucose metabolism from mitochondrial oxidative phosphorylation to glycolysis, even in the presence of oxygen in cancer cells (the Warburg effect), which supports senescence as a tumor suppression mechanism. Overcoming these senescence-associated metabolic alterations may be necessary for cellular transformation.

The nucleolus is the site of ribosome biogenesis, which involves transcription of 47S pre-rRNA by RNA polymerase I, processing of pre-rRNA to 5.8S, 18S and 28S mature rRNAs and assembly of the 40s and 60S ribosomal subunits with ribosomal proteins. The nucleolus also acts as a sensor of cellular stress and couples the cellular stress to the p53 pathway activation, which is the key regulator of senescence. Disruption of nucleolar structures due to changes in rDNA transcription or other stresses may be causally linked to premature senescence induced by oncogene action.

As metabolism is tightly linked to ribosome biogenesis, these two biological processes may be connected each other for both initiation and maintenance of oncogene-induced senescence. Overcoming these shifts in metabolism and ribosome biogenesis could be considered as a fundamental mechanism of tumorigenesis, and investigation of the mechanisms could help to identify a novel strategy to prevent cancer formation.

  1. Hayflick, L. and P.S. Moorhead, The serial cultivation of human diploid cell strains. Exp Cell Res, 1961. 25: p. 585-621.
  2. Serrano, M., et al., Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell, 1997. 88(5): p. 593-602.
  3. Astle, M.V., et al., AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy. Oncogene, 2012. 31(15): p. 1949-62.
  4. Di Micco, R., et al., Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature, 2006. 444(7119): p. 638-42.
  5. Rodier, F. and J. Campisi, Four faces of cellular senescence. J Cell Biol, 2011. 192(4): p. 547-56.
  6. Nacarelli, T. and C. Sell, Targeting metabolism in cellular senescence, a role for intervention. Mol Cell Endocrinol, 2016.
  7. Li, M., et al., Oncogene-induced cellular senescence elicits an anti-Warburg effect. Proteomics, 2013. 13(17): p. 2585-96.
  8. Moss, T., et al., A housekeeper with power of attorney: the rRNA genes in ribosome biogenesis. Cell Mol Life Sci, 2007. 64(1): p. 29-49.
  9. Olson, M.O., Sensing cellular stress: another new function for the nucleolus? Sci STKE, 2004. 2004(224): p. pe10.
  10. Diesch, J., R.D. Hannan, and E. Sanij, Perturbations at the ribosomal genes loci are at the centre of cellular dysfunction and human disease. Cell Biosci, 2014. 4: p. 43.