E2F2 suppresses Myc-induced proliferation and tumorigenesis.

Deregulation of E2F transcriptional activity as a result of alterations in the p16-cyclin D-Rb pathway is a hallmark of cancer. However, the roles of the different E2F family members in the process of tumorigenesis are still being elucidated. Studies in mice and humans suggest that E2F2 functions as a tumor suppressor. Here we demonstrate that E2f2 inactivation cooperates with transgenic expression of Myc to enhance tumor development in the skin and oral cavity. In fact, hemizygosity at the E2f2 locus was sufficient to increase tumor incidence in this model. Loss of E2F2 enhanced proliferation in Myc transgenic tissue but did not affect Myc-induced apoptosis. E2F2 did not behave as a simple activator of transcription in epidermal keratinocytes but instead appeared to differentially regulate gene expression dependent on the individual target. E2f2 inactivation also altered the changes in gene expression in Myc transgenic cells by enhancing the increase of some genes, such as cyclin E, and reversing the repression of other genes. These findings demonstrate that E2F2 can function as a tumor suppressor in epithelial tissues, perhaps by limiting proliferation in response to Myc.

mTORC1-Dependent Metabolic Reprogramming Underlies Escape from Glycolysis Addiction in Cancer Cells.

Although glycolysis is substantially elevated in many tumors, therapeutic targeting of glycolysis in cancer patients has not yet been successful, potentially reflecting the metabolic plasticity of tumor cells. In various cancer cells exposed to a continuous glycolytic block, we identified a recurrent reprogramming mechanism involving sustained mTORC1 signaling that underlies escape from glycolytic addiction. Active mTORC1 directs increased glucose flux via the pentose phosphate pathway back into glycolysis, thereby circumventing a glycolysis block and ensuring adequate ATP and biomass production. Combined inhibition of glycolysis and mTORC1 signaling disrupted metabolic reprogramming in tumor cells and inhibited their growth in vitro and in vivo. These findings reveal novel combinatorial therapeutic strategies to realize the potential benefit from targeting the Warburg effect.

Hepatitis B vaccination in premature and low birth weight (LBW) babies.

OBJECTIVE: To assess the immune response of preterm and low birth weight babies (LBW) to hepatitis B (HB) vaccine. SETTING: Neonatal Intensive Care Unit (NICU), postnatal ward and follow up clinics of KEM Hospital, Pune. DESIGN: Open trial. METHODS: 100 babies were enrolled in four study groups. Group I - preterm, gestational age (GA) < 34 weeks; Group II - GA 34 to 36 weeks; Group III full term <2.5 kg (LBW babies); and Group IV full term >2.5 kg (controls). A recombinant DNA HB vaccine was given at 0, 1, 2 and 12 month schedule. The first injection was administered as soon as the neonate was stabilized. Immune response in terms of anti HBs titres (AUSAB EIA Diagnostic kit) was measured one month after each of the first three injections and at the time of one year booster. Adverse events were monitored. RESULTS: 88 and 62 babies completed the study till the third dose and one year booster dose respectively. Immune response of HB vaccine was uniformly good in all the study groups with 100 % sero-conversion after the second dose itself. By one year (i.e. before the booster dose), very high titres were recorded in all 100%, with 85% demonstrating titres >1000 mIU/ml. Preterm and LBW babies had higher GMT as compared to full term babies till one month after third dose. By one year (before booster), full term babies had higher GMT than preterm and LBW babies. However, these differences were not statistically significant. The vaccine was well tolerated and safe and there were no adverse reactions. CONCLUSION: Immune response of preterm, LBW and full term babies to the new generation recombinant DNA HB vaccine was uniformly good. High and long term seroprotective levels were achieved after the second dose itself.

Acquired resistance of non-small cell lung cancer cells to MET kinase inhibition is mediated by a switch to epidermal growth factor receptor dependency.

Cancer cells harboring MET amplification display striking sensitivity to selective small molecule inhibitors of MET kinase, prompting their clinical evaluation. Similar to the experience with traditional therapeutics, most patients responding to treatment with such molecular targeted therapeutics ultimately relapse with drug-resistant disease. In this study we modeled acquired resistance to experimental MET kinase inhibitor PF2341066 in MET-amplified non-small cell lung carcinoma (NSCLC) cell lines to identify drug resistance mechanisms that may arise in clinic. We found that activation of the epidermal growth factor receptor (EGFR) pathway emerges as a resistance mechanism in MET-amplified cells after prolonged exposure to PF2341066. Whereas combined inhibition of MET and EGFR kinases in MET-dependent NSCLC cells did not enhance their initial sensitivity to PF2341066, this combination dramatically suppressed the eventual emergence of drug-resistant clones after prolonged drug exposure. Conversely, activation of the EGFR pathway increased the yield of PF2341066-resistant clones, confirming the significance of this pathway in conferring resistance. Our findings support an intimate relationship between the EGFR and MET signaling pathways in NSCLC, and they suggest that combination treatment with MET and EGFR kinase inhibitors may be beneficial in MET-amplified NSCLC by reducing selection for drug resistant clones.

Oncogenes and the DNA damage response: Myc and E2F1 engage the ATM signaling pathway to activate p53 and induce apoptosis.

Activation of the ATM DNA damage response pathway is commonly observed in a variety of early-stage neoplasias. It has been proposed that this checkpoint response functions to suppress the development of cancer. A recent report from our laboratory demonstrates that ATM does indeed function to suppress tumorigenesis by responding to at least some oncogenic stresses. Transgenic expression of Myc is found to cause DNA damage in vivo and ATM is shown to respond to this damage by inducing the accumulation and phosphorylation of p53. In the absence of ATM, p53-dependent apoptosis is reduced and epithelial tumorigenesis is accelerated in Myc transgenic mice. Deregulated expression of the E2F1 transcription factor also elicits an ATM-dependent checkpoint response that activates p53 and promotes apoptosis, although the mechanism by which E2F1 and Myc stimulate ATM may differ. These findings have relevance for understanding why the ATM pathway is activated in many human cancers, what generates the selective pressure for p53 inactivation during tumorigenesis, and why AT patients and carriers are predisposed to developing cancer.

ATM promotes apoptosis and suppresses tumorigenesis in response to Myc.

Overexpression of the c-myc oncogene contributes to the development of a significant number of human cancers. In response to deregulated Myc activity, the p53 tumor suppressor is activated to promote apoptosis and inhibit tumor formation. Here we demonstrate that p53 induction in response to Myc overexpression requires the ataxia-telangiectasia mutated (ATM) kinase, a major regulator of the cellular response to DNA double-strand breaks. In a transgenic mouse model overexpressing Myc in squamous epithelial tissues, inactivation of Atm suppresses apoptosis and accelerates tumorigenesis. Deregulated Myc expression induces DNA damage in primary transgenic keratinocytes and the formation of gammaH2AX and phospho-SMC1 foci in transgenic tissue. These findings suggest that Myc overexpression causes DNA damage in vivo and that the ATM-dependent response to this damage is critical for p53 activation, apoptosis, and the suppression of tumor development.