Phosphomevalonate Kinase Controls ß-Catenin Signaling via the Metabolite 5-Diphosphomevalonate.

ß-catenin signaling is abnormally activated in cancer. Here, this work screens the mevalonate metabolic pathway enzyme PMVK to stabilize ß-catenin signaling using a human genome-wide library. On the one hand, PMVK-produced MVA-5PP competitively binds to CKIα to prevent ß-catenin Ser45 phosphorylation and degradation. On the other hand, PMVK functions as a protein kinase to directly phosphorylate ß-catenin Ser184 to increase its protein nuclear localization. This synergistic effect of PMVK and MVA-5PP together promotes ß-catenin signaling. In addition, PMVK deletion impairs mouse embryonic development and causes embryonic lethal. PMVK deficiency in liver tissue alleviates DEN/CCl4 -induced hepatocarcinogenesis. Finally, the small molecule inhibitor of PMVK, PMVKi5, is developed and PMVKi5 inhibits carcinogenesis of liver and colorectal tissues. These findings reveal a non-canonical function of a key metabolic enzyme PMVK and a novel link between the mevalonate pathway and ß-catenin signaling in carcinogenesis providing a new target for clinical cancer therapy.

p53 promotes peroxisomal fatty acid ß-oxidation to repress purine biosynthesis and mediate tumor suppression.

The metabolic pathways through which p53 functions as a potent tumor suppressor are incompletely understood. Here we report that, by associating with the Vitamin D receptor (VDR), p53 induces numerous genes encoding enzymes for peroxisomal fatty acid ß-oxidation (FAO). This leads to increased cytosolic acetyl-CoA levels and acetylation of the enzyme 5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase (ATIC), which catalyzes the last two steps in the purine biosynthetic pathway. This acetylation step, mediated by lysine acetyltransferase 2B (KAT2B), occurs at ATIC Lys 266, dramatically inhibits ATIC activity, and inversely correlates with colorectal cancer (CRC) tumor growth in vitro and in vivo, and acetylation of ATIC is downregulated in human CRC samples. p53-deficient CRCs with high levels of ATIC is more susceptible to ATIC inhibition. Collectively, these findings link p53 to peroxisomal FAO, purine biosynthesis, and CRC pathogenesis in a manner that is regulated by the levels of ATIC acetylation.

[Clinical observation of ankylosing spondylitis treated with moxibustion along the governor vessel and the conception vessel and salazosulfapyridine].

OBJECTIVE: To observe the difference in the clinical efficacy on ankylosing spondylitis (AS) between the combined therapy of moxibustion along the governor vessel and the conception vessel and salazosulfapyridine (SASP) and the routine moxibustion. METHODS: Sixty-two patients of AS were randomized into two groups, 31 cases in each one with one case dnopping separately. In the two groups, SASP was prescribed for oral administration. In the observation group, the self-prepared moxa powder, ginger granules and moxa wool were placed on the back, from Dazhui (GV 14) to Yaoshu (GV 2) and on the abdomen, from the inferior of the xiphoid process to the upper border of symphsis pubis, covering the running of the governor vessel and the conception vessel. In the control group, the routine moxibustion therapy was used, in which, the moxa box was placed on the back and abdomen alternatively. Each treatment lasted 2 h, once every 7 days, 3 treatments as one session. After 3 sessions of treatment, the symptom score, visual analogue scale (VAS) score, time of morning stiffness, Schober test, occiput-to-wall distance and thoracic mobility were observed before and after treatment. The clinical efficacy was evaluated in the two groups. RESULTS: The total effective rate was 86.7% (26/30) in the observation group, better than 73.3% (22/30) in the control group. The efficacy in the observation group was better than that in the control group (P<0.05). All of the observation indices after treatment were improved apparently as compared with those before treatment in the two groups (all P<0.01). After treatment, the improvements in the symptom score, VAS score, time of morning stiffness and Schober test in the observation group were better apparently than those in the control group (all P<0.01). CONCLUSIONS: On the basis of treatment with SASP, moxibustion along the governor vessel and the conception vessel achieves the definite efficacy on AS, better than the routine moxibustion therapy.