Short-term starvation or fasting can augment cancer treatment efficacy, but can also be effective in delaying cancer progression in the absence of chemotherapy. However, the underlying molecular mechanism remains elusive. REV1, a specialized DNA polymerase involved in DNA repair, has emerged as an essential component in genome maintenance and cancer development. Here we describe REV1 as an important signaling node linking nutrient sensing and metabolic control to cell fate. We show that REV1 is a novel binding partner of the tumor suppressor p53 and regulates its activity, and that short-term starvation facilitates the modifications of these proteins. Under starvation, REV1 is modified by SUMO2/3, resulting in consequent relief of REV1’s inhibition of p53 and enhancing p53 activation, pro-apoptotic genes expression and in turn p53-mediated apoptosis in breast cancer and melanoma cells. Thus, fasting, through its effect on REV1, is a promising non-toxic strategy to increase p53-dependent cell death and to enhance the efficacy of cancer therapies.

Acute myeloid leukemia (AML) is a heterogeneous disease in which a variety of distinct genetic alterations might occur. Recent attempts to identify the leukemia stem-like cells (LSC) have also indicated heterogeneity of these cells. On the basis of mathematical modeling and computer simulations, we have provided evidence that proliferation and self-renewal rates of the LSC population have greater impact on the course of disease than proliferation and self-renewal rates of leukemia blast populations, that is, leukemia progenitor cells. The modeling approach has enabled us to estimate the LSC properties of 31 individuals with relapsed AML and to link them to patient survival. On the basis of the estimated LSC properties, the patients can be divided into two prognostic groups that differ significantly with respect to overall survival after first relapse. The results suggest that high LSC self-renewal and proliferation rates are indicators of poor prognosis. Nevertheless, high LSC self-renewal rate may partially compensate for slow LSC proliferation and vice versa. Thus, model-based interpretation of clinical data allows estimation of prognostic factors that cannot be measured directly. This may have clinical implications for designing treatment strategies. Cancer Res; 75(6); 1–10. ©2015 AACR.

Acute myeloid leukemia is a heterogeneous disease in which a variety of distinct genetic alterations occur. Recent studies to identify the leukemia stem-like cells (LSCs) have also indicated heterogeneity of these cells. Based on mathematical modeling and computer simulations we have provided evidence that proliferation and self-renewal rates of the LSC population have greater impact on the course of disease than proliferation and self-renewal rates of leukemia blast populations, i.e. leukemia progenitor cells. The modeling approach has enabled us to estimate the LSC properties of 31 individuals with relapsed AML and to link them to patient survival. Based on the estimated LSC properties the patients can be divided into two prognostic groups which differ significantly with respect to overall survival after first relapse. The results suggest that high LSC self-renewal and proliferation rates are indicators of poor prognosis. Nevertheless, high LSC self-renewal rate may partially compensate for slow LSC proliferation and vice versa. Thus, model-based interpretation of clinical data allows estimation of prognostic factors that cannot be measured directly. This may have clinical implications for designing treatment strategies.

Drinking coffee is associated with a slightly reduced risk for skin cancer, a new study has found.

Genetic mouse studies suggest that the NF-κB pathway regulator NEMO (also known as IKKγ) controls chronic inflammation and carcinogenesis in the liver. However, the molecular mechanisms explaining the function of NEMO are not well defined. Here, we report that overexpression of the cell-cycle regulator p21 is a critical feature of liver inflammation and carcinogenesis caused by the loss of NEMO. NEMOΔhepa mice develop chronic hepatitis characterized by increased hepatocyte apoptosis and proliferation that causes the development of fibrosis and hepatocellular carcinoma (HCC), similar to the situation in human liver disease. Having identified p21 overexpression in this model, we evaluated its role in disease progression and LPS-mediated liver injury in double mutant NEMOΔhepa/p21−/− mice. Eight-week-old NEMOΔhepa/p21−/− animals displayed accelerated liver damage that was not associated with alterations in cell-cycle progression or the inflammatory response. However, livers from NEMOΔhepa/p21−/− mice displayed more severe DNA damage that was further characterized by LPS administration correlating with higher lethality of the animals. This phenotype was attenuated by genetic ablation of the TNF receptor TNF-R1 in NEMOΔhepa/p21−/− mice, demonstrating that DNA damage is induced via TNF. One-year-old NEMOΔhepa/p21−/− mice displayed greater numbers of HCC and severe cholestasis compared with NEMOΔhepa animals. Therefore, p21 overexpression in NEMOΔhepa animals protects against DNA damage, acceleration of hepatocarcinogenesis, and cholestasis. Taken together, our findings illustrate how loss of NEMO promotes chronic liver inflammation and carcinogenesis, and they identify a novel protective role for p21 against the generation of DNA damage. Cancer Res; 75(6); 1–12. ©2014 AACR.