Unité 1065, équipe « contrôle métabolique des morts cellulaires », Institut national de la santé et de la recherche médicale, centre méditerranéen de médecine moléculaire (C3M), 06204 Nice, France.
Ann Endocrinol (Paris). 2013 May;74(2):111-4. doi: 10.1016/j.ando.2013.02.004. Epub 2013 Apr 15.
The transcription factor hypoxia-inducible factor-1 (HIF-1) facilitates the induction of enzymes necessary for regulation of biological processes required for cell survival and the acquisition of an aggressive and invasive phenotype, such as regulation of the intracellular pH (pHi), anaerobic glycolysis, angiogenesis, migration/invasion... In this presentation, we will highlight some of the HIF-1-induced gene products - carbonic anhydrases IX and XII (CAs) and monocarboxylate transporters (MCTs) - which regulate the pHi by controlling export of metabolically-generated acids (carbonic and lactic acids). We reported that targeting these pHi-regulated processes through inhibition of either HIF-1-induced CAIX/CAXII or HIF-1-induced MCT4, MCT1 or Basigin/EMMPRIN/CD147 chaperone of MCTs, severely restricts glycolysis-generated ATP levels and tumor growth. In addition, we demonstrated that the Myc/HIF-1-targeted glyceraldehyde-3-phosphate dehydrogenase (GAPDH) catalyzing a key step producing the NADH cofactor, activates the Akt pathway, thereby upregulating expression of the anti-apoptotic Bcl-xL. As a consequence, high expression of GAPDH contributes to tumor aggressiveness, in particular in the context Myc-driven B lymphomas. We propose that membrane-bound carbonic anhydrases (CAIX, CAXII), monocarboxylate transporters/chaperon Basigin (Myc-induced MCT1 and HIF-induced-MCT4) and GAPDH that are associated with exacerbated tumor metabolism, represent new potential targets for anticancer therapy.
转录因子缺氧诱导因子-1（HIF-1）促进了调节细胞存活和获得侵袭性表型所需的生物过程所需酶的诱导，例如细胞内 pH（pHi）、无氧糖酵解、血管生成、迁移/侵袭等的调节。在本次演讲中，我们将重点介绍一些由 HIF-1 诱导的基因产物——碳酸酐酶 IX 和 XII（CA）和单羧酸转运蛋白（MCT）——通过控制代谢产生的酸（碳酸和乳酸）的外排来调节 pHi。我们报道通过抑制 HIF-1 诱导的 CAIX/CAXII 或 HIF-1 诱导的 MCT4、MCT1 或 Basigin/EMMPRIN/CD147 MCT 伴侣，靶向这些 pHi 调节过程，可严重限制糖酵解产生的 ATP 水平和肿瘤生长。此外，我们证明了 Myc/HIF-1 靶向的甘油醛-3-磷酸脱氢酶（GAPDH）催化产生 NADH 辅助因子的关键步骤，激活 Akt 通路，从而上调抗凋亡 Bcl-xL 的表达。因此，GAPDH 的高表达有助于肿瘤的侵袭性，特别是在 Myc 驱动的 B 淋巴瘤的情况下。我们提出，与加剧的肿瘤代谢相关的膜结合碳酸酐酶（CAIX、CAXII）、单羧酸转运蛋白/伴侣 Basigin（Myc 诱导的 MCT1 和 HIF 诱导的-MCT4）和 GAPDH，代表了新的潜在抗癌治疗靶点。
