Potential role of lipophagy impairment for anticancer effects of glycolysis-suppressed pancreatic ductal adenocarcinoma cells.

Although increased aerobic glycolysis is common in various cancers, pancreatic ductal adenocarcinoma (PDAC) cells can survive a state of glycolysis suppression. We aimed to identify potential therapeutic targets in glycolysis-suppressed PDAC cells. By screening anticancer metabolic compounds, we identified SP-2509, an inhibitor of lysine-specific histone demethylase 1A (LSD1), which dramatically decreased the growth of PDAC PANC-1 cells and showed an anti-tumoral effect in tumor-bearing mice. The growth of glycolysis-suppressed PANC-1 cells was also inhibited by another LSD1 inhibitor, OG-L002. Similarly, the other two PDAC cells (PK-1 and KLM-1) with suppressed glycolysis exhibited anticancer effects against SP-2509. However, the anticancer effects on PDAC cells were unrelated to LSD1. To investigate how PDAC cells survive in a glycolysis-suppressed condition, we conducted proteomic analyses. These results combined with our previous findings suggested that glucose-starvation causes PDAC cells to enhance mitochondrial oxidative phosphorylation. In particular, mitochondrial fatty acid metabolism was identified as a key factor contributing to the survival of PDAC cells under glycolysis suppression. We further demonstrated that SP-2509 and OG-L002 disturbed fatty acid metabolism and induced lipid droplet accumulation through the impairment of lipophagy, but not bulk autophagy. These findings indicate a significant potential association of lipophagy and anticancer effects in glycolysis-suppressed PDAC cells, offering ideas for new therapeutic strategies for PDAC by dual inhibition of glycolysis and fatty acids metabolism.

PINK1-dependent and Parkin-independent mitophagy is involved in reprogramming of glycometabolism in pancreatic cancer cells.

Cancer cells rely on glycolysis to generate ATP for survival. However, inhibiting glycolysis is insufficient for the eradication of cancer cells because glycolysis-suppressed cells undergo metabolic reprogramming toward mitochondrial oxidative phosphorylation. We previously described that upon glycolytic suppression in pancreatic cancer cells, intracellular glycometabolism is shifted toward mitochondrial oxidative phosphorylation in an autophagy-dependent manner for cellular survival. Here, we hypothesized that mitophagy, which selectively degrades mitochondria via autophagy, is involved in mitochondrial activation under metabolic reprogramming. We revealed that glycolytic suppression notably increased mitochondrial membrane potential and mitophagy in a pancreatic cancer cell model (PANC-1). PTEN-induced kinase 1 (PINK1), a ubiquitin kinase that regulates mitophagy in healthy cells, regulated mitochondrial activation through mitophagy by glycolytic suppression. However, Parkin, a ubiquitin ligase regulated by PINK1 in healthy cells to induce mitophagy, was not involved in the PINK1-dependent mitophagy of the cancer glycometabolism. These results imply that cancer cells and healthy cells have different regulatory pieces of machinery for mitophagy, and inhibition of cancer-specific mechanisms may be a potential strategy for cancer therapy targeting metabolic reprogramming.

Usefulness of MR-seminography using Gd-DTPA in intermediate magnetic field MRI equipment.

T(2)-weighted fast advanced spin-echo imaging with gadolinium (hereinafter referred to as "MR-seminography") of the genital tract was evaluated for its usefulness in non-invasive investigation into the morphology of these organs. Twenty healthy male volunteers who are confirmed as free of genital tract obstruction were entered into the study. The genital tract was imaged using the 0.5 T MRI system by fast advanced spin echo (FASE) method. Based on quantitative evaluation, visibility evaluation, and the visualization of the genital tract in each subject, the contrast-enhanced images were assessed in comparison with those at pre-injection of the contrast agent by four specialists. Also examined were the morphology of the seminal vesicle according to age group using "Ishigami-Mori's classification," and the age angle of the main ducts. MR-seminography produced high contrast images and revealed a significantly decreased signal in the pelvic organs under investigation. In the analysis of individual subjects, the area from the proximal portion of the vas deferens to the ampulla and the seminal vesicles was on the whole well visualized except for the distal portion of the vas deferens and the ejaculatory duct. With regard to seminal vesicle morphology, type II was predominant. The age angle showed a trend toward widening with age. MR-seminography is non-invasive, useful, and therefore a highly recommended procedure for observation of the morphology in the area from the proximal portion of the vas deferens to the seminal vesicle.