Retinoblastoma Loss Modulates DNA Damage Response Favoring Tumor Progression

Abstract

Senescence is one of the main barriers against tumor progression. Oncogenic signals in primary cells result in oncogene-induced senescence (OIS), crucial for protection against cancer development. It has been described in premalignant lesions that OIS requires DNA damage response (DDR) activation, safeguard of the integrity of the genome. Here we demonstrate how the cellular mechanisms involved in oncogenic transformation in a model of glioma uncouple OIS and DDR. We use this tumor type as a paradigm of oncogenic transformation. In human gliomas most of the genetic alterations that have been previously identified result in abnormal activation of cell growth signaling pathways and deregulation of cell cycle, features recapitulated in our model by oncogenic Ras expression and retinoblastoma (Rb) inactivation respectively. In this scenario, the absence of pRb confers a proliferative advantage and activates DDR to a greater extent in a DNA lesion-independent fashion than cells that express only HRasV12. Moreover, Rb loss inactivates the stress kinase DDR-associated p38MAPK by specific Wip1-dependent dephosphorylation. Thus, Rb loss acts as a switch mediating the transition between premalignant lesions and cancer through DDR modulation. These findings may have important implications for the understanding the biology of gliomas and anticipate a new target, Wip1 phosphatase, for novel therapeutic strategies.

AMPK Activation by Oncogenesis Is Required to Maintain Cancer Cell Proliferation in Astrocytic Tumors

“…1A). Furthermore, we were unable to detect significant levels of apoptosis and senescence in any of the experimental groups, as it has already been shown (16).…”

“…The care and use of experimental animals was in accordance with institutional guidelines. Cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% FBS and to express HRas V12 and/or Cre-recombinase ecotropic retrovirus were used as previously published (16).…”

p16INK4A mediates age-related changes in mesenchymal stem cells derived from human dental pulp through the DNA damage and stress response

“…Our results investigated a tight association between the aging and stress response proteins that the expression level of HSP60 was diminished with advanced age. Recent studies indicate that DDR plays a critical role in aging processes (Seoane et al, 2008). DNA damage can be found in almost all of the organs of aged mice .…”

Impaired DNA damage response — An Achilles' heel sensitizing cancer to chemotherapy and radiotherapy

“…However, many primary cancers that develop in patients who do not have germline mutations in these genes can also have impaired DDR (Stawinska et al, 2008). In fact, tumor progression is often associated with progressive impairment of DDR (Seoane et al, 2008; Wang and Figg, 2008). Furthermore, in early pre-malignant lesions the oncogene-driven DNA replication causes replication stress in which the stalling of replication forks cause DNA breakage, formation of DSBs and “constitutive” activation of DDR (Bartkova et al, 2005; 2007).…”