Fig. 4: CD44v6 increases the resistance of CRC cells to anti-cancerous therapies.
a CD44v6 is able to increase the resistance of CRC cells to apoptosis. Furthermore, iASPP binds to p53 together with Mdm2 to limit the translocation of p53 into the nucleus to initiate translocation of apoptosis-related genes, such as NOXA and PUMA. Hence, p53-dependent apoptosis is prohibited (see ref. 77) (blue line). Notably, although the C terminus of CD44v6 molecule contains a motif for iASPP binding, the biological effect of this binding remains unclear (denoted by the black question mark). In addition, CD44v6 maintains cell survival by competitively blocking the binding between Fas and their ligands (FasL), because the proximal membrane region encoded by the exon 6 variant provides a platform for Fas binding, which prevents caspase activation to limit cell apoptosis (see ref. 96) (pink line). b CD44v6 is able to promote proliferation among CRC cells. Thus, the interaction between HA and CD44v6 is able to stabilize the cysteine-glutamate exchanger on the cell membrane to increase the cytoplasmic level of cysteine, which then results in a high production of GSH. Therefore, GSH is able to suppress ROS (see ref. 16), protecting CRC cells against ROS-induced cell injury (orange line). In addition, iASPP clears intracellular ROS by binding with Keap1, thus enabling Nrf2 to be stabilized. Nrf2 will then translocate into the nucleus to initiate transcription of genes functioning in promoting cell expansion (see ref. 78) (blue line). c CD44v6 induces chemoresistance by increasing MDR gene expression and MDR activity. In this process, the HA-CD44v6 interaction is able to recruit the PI3K protein to the cytoplasmic domain of the CD44v6 molecule through the GAB1 protein (see ref. 88). By using this action, the PI3K/Akt signaling pathway is thereby activated. Furthermore, the genes encoding MDR and the enzyme engaging in the biosynthesis of HA are targets of the PI3K/Akt signaling pathway. MDR is known to pump intracellular toxins to the outside environment, thus protecting CRC cells against chemical agent-induced death. Moreover, by using the increased production of HA, the above process will be strengthened. d CD44v6 is able to induce chemoresistance by increasing autophagy. The activated CD44v6 will enhance the phosphorylation of both Akt and Erk under cytotoxic stress (see ref. 15). Furthermore, the activation of PI3K/Akt pathway suppresses the rapamycin kinase, which always acts as a negative regulator of autophagy activity (yellow line). Moreover, the activated MAPK/ERK signaling pathway also plays an important role in autophagosome induction (see ref. 15) (red line), which then acts on TGFβ/Smad signaling pathway to drive EMT (green line)
