The Warburg effect in Multiple Myeloma and its microenvironment

This review highlights the current state of knowledge about the metabolism of cancer cells, especially with respect to “Warburg effect” in the pathogenesis of Multiple Myeloma (MM). Various pathways are known to contribute to the Warburg effect, characterized by an increased anaerobic glycolysis rather than mitochondrial oxidative phosphorylation (OXPHOS), resulting in elevated levels of lactic acid even in the presence of sufficient oxygen. For one thing it was shown, activation of PI3K/Akt/mTOR leads to enhanced expression of nutrient transporters and stimulation of glycolysis. In particular, glucose transporter (GLUT) 1, 4, 8 as well as 11 show elevated expression in MM and therefore enhanced glycolytic flux as well. Another important route manifesting the Warburg effect is peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and its dual role within the production of reactive oxygen species (ROS). Furthermore, the stabilization and transcription of hypoxia-inducible factor 1 α (HIF1α) under tumor-attributed hypoxic conditions shows promising downstream mechanisms such as histone deacetylase (HDAC), which can be targeted and serve as adjuvant therapy to prolong overall survival of MM patients. In this paper we review the most promising and researched targets of the Warburg signaling are represented and analyzed upon their suitability as a therapeutic target in MM.