Regulation of energy metabolism is a novel function of p53 in tumor suppression. Parkin (PARK2), a Parkinson disease-associated gene, is a potential tumor suppressor whose expression is frequently diminished in tumors. Here Parkin was identified as a p53 target gene that is an important mediator of p53's function in regulating energy metabolism. The human and mouse Parkin genes contain functional p53 responsive elements, and p53 increases the transcription of Parkin in both humans and mice. Parkin contributes to the function of p53 in glucose metabolism; Parkin deficiency activates glycolysis and reduces mitochondrial respiration, leading to the Warburg effect. Restoration of Parkin expression reverses the Warburg effect in cells. Thus, Parkin deficiency is a novel mechanism for the Warburg effect in tumors. Parkin also contributes to the function of p53 in antioxidant defense. Furthermore, Parkin deficiency sensitizes mice to γ-irradiation-induced tumorigenesis, which provides further direct evidence to support a role of Parkin in tumor suppression. Our results suggest that as a novel component in the p53 pathway, Parkin contributes to the functions of p53 in regulating energy metabolism, especially the Warburg effect, and antioxidant defense, and thus the function of p53 in tumor suppression. Metabolic alterations are a hallmark of tumor cells (1, 2). Whereas normal cells use mitochondrial respiration to provide energy, the majority of tumor cells preferentially use aerobic glycolysis, a switch known as the Warburg effect (3). Because glycolysis produces ATP much less efficiently than mitochondrial respiration, tumor cells compensate by having a much higher rate of glucose uptake and utilization than normal cells (1, 2). Recent studies have strongly suggested that the Warburg effect is a key contributor to malignant progression (1, 2), and reversing the Warburg effect inhibits the tumorigenicity of cancer cells (4, 5). However, the underlying mechanisms for the Warburg effect are not well-understood (1, 2).p53 plays a central role in tumor prevention. As a transcription factor, in response to stress, p53 transcribes its target genes to start various cellular responses, including cell-cycle arrest, apoptosis, and/or senescence, to prevent tumor formation (6, 7). Recent studies have revealed that regulating energy metabolism and the Warburg effect is a novel function of p53 in tumor suppression (2, 8). p53 induces TIGAR (TP53-induced glycolysis and apoptosis regulator) to reduce glycolysis (9), and induces SCO2 (10) and GLS2 (11, 12) to promote mitochondrial respiration. Loss of p53 results in decreased mitochondrial respiration and enhanced glycolysis, leading to the Warburg effect. Furthermore, regulating antioxidant defense has recently been revealed as another novel function for p53 (8, 13). p53 induces several antioxidant genes, including Sestrins (14), TIGAR (9), ALDH4 (15), and GLS2 (11, 12), to reduce the levels of reactive oxygen species (ROS) and DNA damage in cells, which contributes greatly to the ro...

The mechanistic target of rapamycin (mTOR) integrates growth factor signals with cellular nutrient and energy levels and coordinates cell growth, proliferation and survival. A regulatory network with multiple feedback loops has evolved to ensure the exquisite regulation of cell growth and division. Colorectal cancer is the most intensively studied cancer because of its high incidence and mortality rate. Multiple genetic alterations are involved in colorectal carcinogenesis, including oncogenic Ras activation, phosphatidylinositol 3-kinase pathway hyperactivation, p53 mutation, and dysregulation of wnt pathway. Many oncogenic pathways activate the mTOR pathway. mTOR has emerged as an effective target for colorectal cancer therapy. In vitro and preclinical studies targeting the mTOR pathway for colorectal cancer chemotherapy have provided promising perspectives. However, the overall objective response rates in major solid tumors achieved with single-agent rapalog therapy have been modest, especially in advanced metastatic colorectal cancer. Combination regimens of mTOR inhibitor with agents such as cytotoxic chemotherapy, inhibitors of vascular endothelial growth factor, epidermal growth factor receptor and Mitogen-activated protein kinase kinase (MEK) inhibitors are being intensively studied and appear to be promising. Further understanding of the molecular mechanism in mTOR signaling network is needed to develop optimized therapeutic regimens. In this paper, oncogenic gene alterations in colorectal cancer, as well as their interaction with the mTOR pathway, are systematically summarized. The most recent preclinical and clinical anticancer therapeutic endeavors are reviewed. New players in mTOR signaling pathway, such as non-steroidal anti-inflammatory drug and metformin with therapeutic potentials are also discussed here.

SOD1 is known as the major cytoplasmic superoxide dismutase and an anticancer target. However, the role of SOD1 in cancer is not fully understood. Herein we describe the generation of an inducible Sod1 knockout in KRAS-driven NSCLC mouse model. Sod1 knockout markedly reduces tumor burden in vivo and blocks growth of KRAS mutant NSCLC cells in vitro. Intriguingly, SOD1 is enriched in the nucleus and notably in the nucleolus of NSCLC cells. The nuclear and nucleolar, not cytoplasmic, form of SOD1 is essential for lung cancer cell proliferation. Moreover, SOD1 interacts with PeBoW complex and controls its assembly necessary for pre-60S ribosomal subunit maturation. Mechanistically, SOD1 regulates co-localization of PeBoW with and processing of pre-rRNA, and maturation of cytoplasmic 60S ribosomal subunits in KRAS mutant lung cancer cells. Collectively, our study unravels a nuclear SOD1 function essential for ribosome biogenesis and proliferation in KRAS-driven lung cancer.

SUMMARY Rab1A is a small GTPase known for its role in vesicular trafficking. Recent evidence indicates that Rab1A is essential for amino acids (aas) sensing and signaling to regulate mTORC1 in normal and cancer cells. However, Rab1A’s in vivo function in mammals is not known. Here, we report the generation of tamoxifen (TAM)-induced whole body Rab1A knockout (Rab1A −/− ) in adult mice. Rab1A −/− mice are viable but become hyperglycemic and glucose intolerant due to impaired insulin transcription and β-cell proliferation and maintenance. Mechanistically, Rab1A mediates AA-mTORC1 signaling, particularly branched chain amino acids (BCAA), to regulate the stability and localization of the insulin transcription factor Pdx1. Collectively, these results reveal a physiological role of aa-Rab1A-mTORC1 signaling in the control of whole-body glucose homeostasis in mammals. Intriguingly, Rab1A expression is reduced in β-cells of type 2 diabetes (T2D) patients, which is correlated with loss of insulin expression, suggesting that Rab1A downregulation contributes to T2D progression.

SUMMARY Protein kinases are therapeutic targets for human cancer. However, “gatekeeper” mutations in tyrosine kinases cause acquired clinical resistance, limiting long-term treatment benefits. mTOR is a key cancer driver and drug target. Numerous small molecule mTOR kinase inhibitors have been developed, with some already in human clinical trials. Given our clinical experience with targeted therapeutics, acquired drug resistance in mTOR is thought likely but not yet documented. Herein, we describe identification of a hotspot (L2185) for drug-resistant mutations, which is distinct from the “gatekeeper” site, and a chemical scaffold refractory to drug-resistant mutations. We also provide new insights into mTOR kinase structure and function. The hotspot mutations are potentially useful as surrogate biomarkers for acquired drug resistance in ongoing clinical trials and future treatments, and to facilitate design of the next generation of mTOR-targeted drugs. Our study provides a foundation for further research on mTOR kinase function and targeting.