Fig. 4: Mechanisms of chemoresistance in cancer stem cells.

Upon p38 activation, CSCs are maintained in a non-proliferating, quiescent state for long periods, thus escaping chemotherapies that target rapidly dividing cells. p38 regulates the expression of ALDHs, such as ALDH2, which detoxify the metabolites of chemotherapeutic agents, rendering them ineffective. The WNT/β-catenin signaling pathway, promoted by p38, mediates chemoresistance via the upregulation of ABC transporter pumps such as ABCC1, ABCG2, and MDR1, which remove chemotherapy agents from inside the cell. These ABC transporters are also directly upregulated by p38. Moreover, the Notch and NF-κB signaling axes promote self-renewal and inhibit apoptosis of CSCs even in the presence of chemotherapy drugs. The activity of NF-κB is stimulated by p38, and Notch activates p38. Additionally, p38 phosphorylates BCL-2, promoting apoptosis.