p38α MAPK pathway: A key factor in colorectal cancer therapy and chemoresistance

Abstract

Colorectal cancer (CRC) remains one of the most common malignancies in the world. Although surgical resection combined with adjuvant therapy is effective at the early stages of the disease, resistance to conventional therapies is frequently observed in advanced stages, where treatments become ineffective. Resistance to cisplatin, irinotecan and 5-fluorouracil chemotherapy has been shown to involve mitogen-activated protein kinase (MAPK) signaling and recent studies identified p38α MAPK as a mediator of resistance to various agents in CRC patients. Studies published in the last decade showed a dual role for the p38α pathway in mammals. Its role as a negative regulator of proliferation has been reported in both normal (including cardiomyocytes, hepatocytes, fibroblasts, hematopoietic and lung cells) and cancer cells (colon, prostate, breast, lung tumor cells). This function is mediated by the negative regulation of cell cycle progression and the transduction of some apoptotic stimuli. However, despite its anti-proliferative and tumor suppressor activity in some tissues, the p38α pathway may also acquire an oncogenic role involving cancer related-processes such as cell metabolism, invasion, inflammation and angiogenesis. In this review, we summarize current knowledge about the predominant role of the p38α MAPK pathway in CRC development and chemoresistance. In our view, this might help establish the therapeutic potential of the targeted manipulation of this pathway in clinical settings.

The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer

“…55 The ultimate effect of p38 MAPK activation depends on the type of stimulus in a cell-type-specific manner. [56][57][58] To further explore the role of p38 activation in response to VX680 treatment, we treated cells with BIRB796. BIRB796 is a novel p38 MAPK inhibitor that inhibits all p38 MAPK isoforms in vitro and vivo.…”

Triptolide induces autophagy and apoptosis through ERK activation in human breast cancer MCF‑7 cells

“…TPI affects cell proliferation, growth and apoptosis through upregulating apoptosis protein expression, inducing cell cycle arrest, inhibiting tumor angiogenesis and inducing autophagy. TPI has significant anti-tumor effects on various types of cancer cell in vitro and in vivo, owing to its induction of cell death, and has been found to be effective in lung cancer (8), prostate cancer (9), colon carcinoma (10,11), and others. TPI also shows potent biological effects, such as reduction of inflammatory and immunosuppression.…”

“…Mitogen-activated protein kinases (MAPK) are involved in mediating cell survival (11). The role of extracellular signal-regulated kinase (Erk) phosphorylation in cell proliferation and death is controversial (16,17).…”

Interleukin-37: A crucial cytokine with multiple roles in disease and potentially clinical therapy (Review)

“…The mitogen activated protein kinases (MAPK) signal pathway is one of the main signaling pathways involved in immune responses, with vital roles in the regulation of cytokine and chemokine responses (32). There are three main components in the MAPK signaling pathway: The Jun N-terminal kinase (JNK 1/2/3), extracellular signal-regulated kinase (ERK1/2, ERK 3/4, ERK5, ERK 7/8,) and p38 MAPKs (p38α/β/γ/δ) (33)(34)(35)(36). Once stimulated, the MAPKs, which are expressed in all cell types, are activated and participate in various physiological and biologic processes including inflammation, growth, differentiation, survival and apoptosis of cells (35)(36)(37).…”

“…There are three main components in the MAPK signaling pathway: The Jun N-terminal kinase (JNK 1/2/3), extracellular signal-regulated kinase (ERK1/2, ERK 3/4, ERK5, ERK 7/8,) and p38 MAPKs (p38α/β/γ/δ) (33)(34)(35)(36). Once stimulated, the MAPKs, which are expressed in all cell types, are activated and participate in various physiological and biologic processes including inflammation, growth, differentiation, survival and apoptosis of cells (35)(36)(37). Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that play important roles in intracellular signal transduction and regulation of inflammatory and immune processes (38,39).…”