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Review
. 2020 Aug 17;13(1):113.
doi: 10.1186/s13045-020-00949-4.

The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy

Jimin Yuan  1   2 , Xiaoduo Dong  3 , Jiajun Yap  4 , Jiancheng Hu  5   6
Affiliations
Review

The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy

Jimin Yuan et al. J Hematol Oncol. .

Abstract

Cancer is characterized as a complex disease caused by coordinated alterations of multiple signaling pathways. The Ras/RAF/MEK/ERK (MAPK) signaling is one of the best-defined pathways in cancer biology, and its hyperactivation is responsible for over 40% human cancer cases. To drive carcinogenesis, this signaling promotes cellular overgrowth by turning on proliferative genes, and simultaneously enables cells to overcome metabolic stress by inhibiting AMPK signaling, a key singular node of cellular metabolism. Recent studies have shown that AMPK signaling can also reversibly regulate hyperactive MAPK signaling in cancer cells by phosphorylating its key components, RAF/KSR family kinases, which affects not only carcinogenesis but also the outcomes of targeted cancer therapies against the MAPK signaling. In this review, we will summarize the current proceedings of how MAPK-AMPK signalings interplay with each other in cancer biology, as well as its implications in clinic cancer treatment with MAPK inhibition and AMPK modulators, and discuss the exploitation of combinatory therapies targeting both MAPK and AMPK as a novel therapeutic intervention.

Keywords: AMPK activators; AMPK inhibitors; AMPK signaling; Autophagy; Cellular metabolism; Interplay; RAF/MEK/ERK inhibitors; Ras/RAF/MEK/ERK signaling; Targeted therapy; Tumorigenesis.

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Conflict of interest statement

The authors declare that they have no competing interests. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Fig. 1
Fig. 1
Target hyperactive Ras/RAF/MEK/ERK (MAPK) signaling for cancer therapy. The Ras/RAF/MEK/ERK (MAPK) signaling functions downstream of receptor tyrosine kinases (RTKs). Upon engagement by their ligands, RTKs activates guanine exchange factors, Sos proteins, which load GTP to Ras GTPases. Then, GTP-bound Ras GTPases recruit RAF/MEK heterodimers in cytosol to plasma membrane where they form transient tetramers through the side-to-side dimerization of RAFs. The RAF dimerization not only turns on RAFs but also loosens RAF/MEK heterodimerization and facilitates MEK homodimerization on RAF dimer surface, which leads to the activation of MEKs by RAFs. Once MEKs are activated, they phosphorylate ERKs, and then active ERKs phosphorylate a number of downstream effectors. In cancer cells, hyperactive Ras/RAF/MEK/ERK (MAPK) signaling arising from genetic mutations of Ras GTPases and BRAF can be targeted by small molecular inhibitors of Ras G12C, BRAF(V600E), MEK, and ERK
Fig. 2
Fig. 2
AMPK signaling and its downstream effectors. AMPK is activated by liver kinase B1 (LKB1) or calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2/β) through phosphorylation on Thr172 of α subunit and is inactivated through dephosphorylation of this site by protein phosphatases in response to changes of cellular AMP:ADP:ATP ratio. Downstream effectors activated by AMPK are indicated as arrows, and those inhibited by AMPK are shown as bar-headed lines
Fig. 3
Fig. 3
AMPK signaling is inhibited by hyperactive Ras/RAF/MEK/ERK (MAPK) signaling in cancers. a In BRAF(V600E)-harboring cancers, hyperactive ERKs and downstream RSKs phosphorylate LKB1 on Ser325 and Ser428 sites, which inactivates LKB1 and thus blocks the activation of AMPK by LKB1. b In Ras-mutated cancers, the activity of AMPK is partially inhibited likely by hyperactive MAPK signaling, though the underlying molecular mechanism remains ambiguous. However, this moderate AMPK activity is indispensable for disease progression in Ras-mutated cancers
Fig. 4
Fig. 4
AMPK regulates differentially hyperactive Ras/RAF/MEK/ERK (MAPK) signaling in Ras- versus BRAF(V600E)-mutated cancers. a In Ras-mutated cancers, the C-terminal 14-3-3 binding site of CRAF is phosphorylated by AMPK, which facilitates CRAF dimerization through improving the association of CRAF dimer with 14-3-3 dimer and thus elevates the activity of CRAF, particularly upon RAF inhibitor treatment or metabolic stress. Under these conditions, CRAF forms homodimers with itself or heterodimers with KSR or BRAF. b In BRAF(V600E)-harboring cancers, AMPK phosphorylates the C-terminal 14-3-3 binding site of BRAF(V600E), which prevents BRAF(V600E) dimerization with KSR through enhancing the association of a single BRAF(V600E) molecule with 14-3-3 dimer and thus blocks the activity of BRAF(V600E) upon metabolic stress
Fig. 5
Fig. 5
Combinatorial targeting of hyperactive Ras/RAF/MEK/ERK (MAPK) signaling and AMPK-mediated autophagy to treat Ras/RAF-mutated cancers. Blocking hyperactive Ras/RAF/MEK/ERK (MAPK) signaling by MAPK inhibitors in Ras/RAF-mutated cancer cells elevates autophagic flux through relieving LKB1/AMPK/ULK1 axis and inhibiting glycolysis and mitochondrial functions, which leads to drug tolerance and/or acquired resistance. Combinatorial inhibition of both hyperactive MAPK signaling and autophagy remarkably improves therapeutic efficacy of drugs against these cancers
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