The caspase‐3/p120 RasGAP stress‐sensing module reduces liver cancer incidence but does not affect overall survival in gamma‐irradiated and carcinogen‐treated mice

• Published in: Molecular carcinogenesis 2017-06, Vol.56 (6), p.1680-1684
• Main Authors: Vanli, Güliz, Sempoux, Christine, Widmann, Christian
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Carcinogens; Caspase; Caspase 3 - metabolism; Caspase-3; Cell Line; Ethyl nitrosourea; Ethylnitrosourea; Gamma irradiation; Gamma Rays; Genetic transformation; Homeostasis; Incidence; Initiators; Irradiation; Knock; Liver; Liver - metabolism; Liver - pathology; Liver - radiation effects; Liver cancer; Liver Neoplasms - chemically induced; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Mice; Mice, Inbred C57BL; Mutation; Neoplasms, Radiation-Induced - metabolism; Neoplasms, Radiation-Induced - pathology; Organs; p120 GTPase Activating Protein - metabolism; p120 RasGAP; Point mutation; Rodents; Senescence; Stress; stress‐sensor module; Survival; Tissues; Transformations; Tumorigenesis; Tumors
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.22624

Activation of oncogenes is the initial step in cellular transformation. Oncogenes favor aberrant proliferation, which, at least initially, induces cellular stress. This oncogenic stress can act as a safeguard mechanism against further transformation by inducing senescence or apoptosis. Yet, the few premalignant cells that tolerate and escape these senescent or apoptotic responses are those that will ultimately generate tumors. The caspase‐3/p120 RasGAP module is a stress‐sensing device that promotes survival under mild stress conditions. A point mutation in RasGAP that prevents its cleavage by caspase‐3 inactivates the pro‐survival capacity of the device. When the mice homozygous for this mutation (D455A knock‐in mice) are patho‐physiologically challenged, they experience much stronger cellular damage than their wild‐type counterparts and the affected organs rapidly lose their functionality. We reasoned that the caspase‐3/p120 RasGAP module could help premalignant cells to cope with oncogenic stress and hence favor the development of tumors. Using gamma‐irradiation and N‐ethyl‐N‐nitrosourea (ENU) as tumor initiators, we assessed the survival advantage that the caspase‐3/p120 RasGAP module could provide to premalignant cells. No difference in overall mortality between wild‐type and D455A knock‐in mice were observed. However, the number of ENU‐induced liver tumors in the knock‐in mice was higher than in control mice. These results indicate that the caspase‐3/p120 RasGAP stress‐sensing module impacts on carcinogen‐induced liver cancer incidence but not sufficiently so as to affect overall survival. Hence, gamma irradiation and ENU‐induced tumorigenesis processes do not critically rely on a survival mechanism that contributes to the maintenance of organ homeostasis in stressed healthy tissues.