Role of p38 MAP kinase in cancer stem cells and metastasis

Abstract

Therapeutic resistance and metastatic progression are responsible for the majority of cancer mortalities. In particular, the development of resistance is a significant barrier to the efficacy of cancer treatments such as chemotherapy, radiotherapy, targeted therapies, and immunotherapies. Cancer stem cells (CSCs) underlie treatment resistance and metastasis. p38 mitogen-activated protein kinase (p38 MAPK) is downstream of several CSC-specific signaling pathways, and it plays an important role in CSC development and maintenance and contributes to metastasis and chemoresistance. Therefore, the development of therapeutic approaches targeting p38 can sensitize tumors to chemotherapy and prevent metastatic progression.

Fig. 1. Functions of p38.

A p38 enables cells to respond to various stimuli, including DNA damaging agents, cytokines, heat shock, and oxidative stress. B In addition, p38 affects cell proliferation, cell differentiation, apoptosis, autophagy, and tumor growth in ways dependent on cell type and the signaling pathways involved.

Fig. 2. Domain structures of p38 isoforms.

A Expression sites of different p38 isoforms. B p38ɑ and p38β share more sequence homology with each other than with p38γ and p38δ.

Fig. 3. Schematic of the p38-FOXC2 signaling axis.

The p38-FOXC2 signaling axis is critical in the formation of CSCs. p38, regulated by many upstream kinases, phosphorylates FOXC2, which then activates ZEB1. Activated FOXC2 and ZEB1 promote the EMT, initiating metastasis and conferring stemness in cancer cells. p38 inhibition reverses the EMT and inhibits stemness in cancer cells.

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.

Fig. 5. p38 inhibition sensitizes tumor cells to standard chemotherapy.

Schematic of the effects of A chemotherapy alone, B pre-treatment with the p38 inhibitor SB203580 followed by chemotherapy, and C co-treatment with the p38 inhibitor SB203580 and chemotherapy. The combination treatments overcome the chemoresistance of tumor cells by inhibiting the formation of CSCs and decreasing cell viability and tumorigenicity. This can lead to lower rates of cancer recurrence and higher survival rates.