Norisuke Shibuya

Augmented Pentose Phosphate Pathway Plays Critical Roles in Colorectal Carcinomas

Glycolysis and the pentose phosphate pathway (PPP) are preferentially activated in cancer cells. Accumulating evidence indicated the significance of the altered glucose metabolism in cancer, but the implication for oncotherapy remains unclear. Here we report that the synthesis of glycolytic and PPP enzymes is almost ubiquitously augmented in colorectal carcinoma (CRC) specimens. The mammalian target of rapamycin (mTOR) inhibitor INK128 (300 nM) and phytochemical Avemar (1 mg/ml) inhibited the synthesis of PPP enzymes in CRC cell lines. INK128 (150-600 nM) and resveratrol (75-300 μM) inhibited aerobic glycolysis in the cell lines. INK128 (300 nM) and Avemar (1 mg/ml) decreased the NADPH/NADP+ ratio as well as the GSH/GSSG ratio in the cell lines. Finally, per os administration of INK128 (0.8 mg/kg) or Avemar (1 g/kg) suppressed tumor growth and delayed tumor formation by transplantable CRC specimens derived from patients. Taken together, pharmacological inhibition of the mTOR-PPP axis is a promising therapeutic strategy against CRCs.

Accumulation of phosphorylated p62 is associated with NF-E2-related factor 2 activation in hepatocellular carcinoma.

Frequent alterations are observed in glucose metabolism in hepatocellular carcinoma (HCC). Activation of various enzymes, including ones involved in the pentose phosphate pathway, by NF‐E2‐related factor 2 (NRF2), controls redox homeostasis in HCC. However, the mechanisms mediating NRF2 activation remain unclear. Here, we aimed to investigate the correlation between NRF2, Kelch‐like ECH‐associated protein 1 (KEAP1) syntheses and p62 phosphorylation in HCC.

Preoperative hypoalbuminemia is an independent risk factor for conversion from laparoscopic to open cholecystectomy in patients with cholecystolithiasis.

Laparoscopic cholecystectomy (LC) is regarded as the first choice for patients with cholecystolithiasis, but some patients require conversion to open cholecystectomy (OC) because of inflammation‐related incidents. Therefore, the aim of this study is to explore the risk factors for conversion to OC in patients undergoing elective LC for cholecystolithiasis.

A high preoperative Glasgow prognostic score predicts a high likelihood of conversion from laparoscopic to open surgery in patients with colon cancer

BackgroundAlthough the use of laparoscopic resection for colon cancer (LRC) has been increasing, conversion to open surgery sometimes becomes necessary because of intraoperative difficulties. Although the Glasgow prognostic score (GPS) is well known to be a predictor of outcome in patients with various cancers, it is unclear whether the preoperative GPS can predict the need for conversion from laparoscopic to open surgery.ObjectiveTo investigate factors predictive of conversion from laparoscopic to open surgery in patients with colon cancer.MethodsData from 308 consecutive patients who underwent LRC between January 2006 and March 2017 were retrospectively enrolled. Preoperative clinical factors in patients who had undergone LRC were compared between conversion and non-conversion groups, and multivariate regression analysis was performed to identify preoperative factors that might predict conversion from laparoscopic to open surgery.ResultsAmong 308 patients who had undergone LRC, conversion to open surgery was necessary in 28 (9.1%). Sixteen of the latter patients (6.8%) had GPS 0 (among a total of 234) and 6 (11.5%) had GPS 1 (among a total of 52). The proportion of patients with GPS 2 who required conversion was 27.2% (6/22), which was significantly higher than for those with GPS 0 or 1. Multivariate analysis demonstrated that GPS 2 (odds ratio [OR] 3.352; 95% confidence interval [CI] 1.049–10.71; p = 0.041) and preoperative ileus (OR 7.405; 95% CI 2.386–22.98; p = 0.001) were independent factors predictive of conversion from laparoscopic to open surgery.ConclusionsA high preoperative GPS is an independent factor predictive of conversion from laparoscopic to open surgery in patients with colon cancer.

Preoperative globulin-to-albumin ratio predicts outcome after curative resection in patients with gastric cancer

The globulin‐to‐albumin ratio (GAR) is useful for prognostication of patients with various cancers. However, the significance of GAR in gastric cancer (GC) remains unclear. Our purpose was to investigate the relationship between the GAR and outcome after curative resection in GC patients.

Clinical significance of the globulin-to-albumin ratio for prediction of postoperative survival in patients with colorectal cancer

A previous study has revealed that the albumin/globulin ratio (GAR) before treatment is a predictor of cancer‐specific survival in patients with colorectal cancer (CRC). The aim of the present study was to investigate the clinical significance of GAR for prediction of postoperative survival in patients with CRC.

Metabolic Shunt Pathways, Carcinoma, and mTOR

Abstract Mammalian target of rapamycin (mTOR) has been attracting attention as an oncogene because of its pivotal roles in oncogene/tumor suppressor networks. The upstream negative regulator of mammalian target of rapamycin complex 1 (mTORC1) is tuberous sclerosis complex 2 (TSC2) and TSC2 per se is identified as a tumor suppressor. Moreover, TSC2 is a switch hub which integrates distinct oncogene cascades such as the RAS/RAF/mitogen-activated protein kinase pathway and phosphatidylinositol-4,5-bisphospate 3-kinase-protein kinase B pathway. Rapamycin, from which mTOR derives its name, has been approved as an anticancer agent for specific solid tumors, including renal cell carcinoma. mTORC1 has diverse functions as an oncogene through selective elongation of mRNA (e.g., cyclin D1, vasucular endothelial growth factor, B-cell lymphoma 2, survivin) and via transcription factor hypoxia inducible factor 1-alpha. Tumor cells have long been known to selectively activate glycolysis and shut down oxidative phosphorylation (aerobic glycolysis or called the Warburg effect). One of the implications of the Warburg effect is to decrease the intracellular reactive oxygen species (ROS). The pentose phosphate pathway (PPP) is a glycolysis shunt and has two important functions. One is the anabolic reaction for DNA/RNA synthesis, and the other is to recycle oxidized NADP + to reduced NADPH. NADPH, in turn, drives counter-ROS defense systems, glutathione and thioredoxin. Thus, one reason why cancer cells enormously consume glucose is to drive glutathione and thioredoxin systems through PPP reaction. Indeed, we have observed that enzymes involved in the PPP are frequently increased in hepatocellular and colorectal carcinomas, and that the catalytic inhibitor of mTOR inhibits the tumor colonization of patients’ derived tumor xenografts. Here we discuss the relationship between mTORC1 and cancer, and, in particular, in the context of Warburg effects, PPP, redox regulation, tumor initiating cells (also called cancer stem cells), colonization, and recurrence after surgery.