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. 2015 Jan 20;6(3):276–286. doi: 10.7150/jca.10879

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Schematic diagram of possible apoptotic mechanism underlying EMMPRIN down-regulation via scFv-M6-1B9 intrabody. (A) EMMPRIN facilitates proper expression of MCT1 at the cell surface. This association plays an important functional role in lactate transport. In cancer cells, an excess of lactic acid is produced by aerobic glycolysis, which must be rapidly exported across the plasma membrane to avoid a drop in pH_i ⁵⁷, ⁶⁵. (B) The scFv-M6-1B9 intrabody can specifically trap the EMMPRIN molecule within the ER, based on the ER retention signal. Suppression of EMMPRIN-MCT1 complex by the down-regulation of EMMPRIN, which resulted in the inhibition of the lactate transporter. (C) Blocking of lactate transport leads to the accumulation of intracellular lactate inside the cell ³¹. The acidic pH_i can be stimulated by different pathways, which are as follows: (i) by altering the mitochondrial membrane potential (Δψm) directly or by increasing the permeability of the outer mitochondrial membrane by promoting the binding of Bcl-2 ⁶²; (ii) by activating nuclear localized endonucleases, a key enzyme that mediates regulated DNA fragmentation and chromatin condensation in response to apoptotic signals ⁶³; and (iii) by activating caspase-3, a pro-apoptotic cysteine protease involved in the activation cascade of caspases responsible for apoptosis execution ⁶⁴.

Schematic diagram of possible apoptotic mechanism underlying EMMPRIN down-regulation via scFv-M6-1B9 intrabody. (A) EMMPRIN facilitates proper expression of MCT1 at the cell surface. This association plays an important functional role in lactate transport. In cancer cells, an excess of lactic acid is produced by aerobic glycolysis, which must be rapidly exported across the plasma membrane to avoid a drop in pH_i ⁵⁷, ⁶⁵. (B) The scFv-M6-1B9 intrabody can specifically trap the EMMPRIN molecule within the ER, based on the ER retention signal. Suppression of EMMPRIN-MCT1 complex by the down-regulation of EMMPRIN, which resulted in the inhibition of the lactate transporter. (C) Blocking of lactate transport leads to the accumulation of intracellular lactate inside the cell ³¹. The acidic pH_i can be stimulated by different pathways, which are as follows: (i) by altering the mitochondrial membrane potential (Δψm) directly or by increasing the permeability of the outer mitochondrial membrane by promoting the binding of Bcl-2 ⁶²; (ii) by activating nuclear localized endonucleases, a key enzyme that mediates regulated DNA fragmentation and chromatin condensation in response to apoptotic signals ⁶³; and (iii) by activating caspase-3, a pro-apoptotic cysteine protease involved in the activation cascade of caspases responsible for apoptosis execution ⁶⁴.