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Abstract
Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Here, we focus on the role of MAPK pathways in modulating drug sensitivity and resistance in cancer. We briefly discuss new findings in the extracellular signaling-regulated kinase (ERK) pathway, but mainly focus on the mechanisms how stress activated MAPK pathways, such as p38 MAPK and the Jun N-terminal kinases (JNK), impact the response of cancer cells to chemotherapies and targeted therapies. In this context, we also discuss the role of metabolic and epigenetic aberrations and new therapeutic opportunities arising from these changes.
Highlights
Mitogen-activated protein kinase (MAPK) pathways are cascades of three kinases, where the most upstream kinase (MAPKKK)responds to various extra- and intracellular signals and activates the middle kinase (MAPKK) by direct phosphorylation
We focus on discussing less well reviewed areas of MAPK signaling and their relevance to drug resistance, i.e., the Jun N-terminal kinases (JNK) and p38 MAPK pathways, as well as epigenetic and metabolic changes linked to MAPK signaling
Deletion of the CD36 gene in a mouse model of breast cancer significantly attenuated mammary tumor development [166]. These results suggest that CD36 along with other fatty acid (FA) transporters may play a role in the acquired resistance mechanisms of cancer cells
Summary
MAPK pathways are cascades of three kinases, where the most upstream kinase (MAPKKK). MAPK substrate phosphorylation often includes the inhibition of upstream activators This configuration corresponds to a negative feedback amplifier that combines signal amplification through the 3-tiered kinase cascade with a negative feedback from the output back to the input signal, thereby ensuring robustness against noise and graded responses [2]. MAPKs react to a wide variety of input signals including physiological cues such as hormones, cytokines, and growth factors, as well as endogenous stress and environmental signals They are traditionally classified in mitogen and stress activated MAPKs, with classic representatives being ERK as mitogen responsive and JNK and p38 as stress responsive MAPKs. Physiologically, the distinction is blurry with all three families responding to a wide and overlapping variety of signals. We focus on discussing less well reviewed areas of MAPK signaling and their relevance to drug resistance, i.e., the JNK and p38 MAPK pathways, as well as epigenetic and metabolic changes linked to MAPK signaling
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