Targeting ERK-Hippo Interplay in Cancer Therapy

Vališ, Karel; Novák, Petr

doi:10.3390/ijms21093236

Cited by 21 publications

(18 citation statements)

References 134 publications

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“…On the other hand, active MAPK signaling also turns on some negative feedback loops, which help cells return to quiescent status [56][57][58]. An aberrant activation of MAPK signaling frequently induces human cancers or developmental disorders, though an extremely high MAPK signaling may induce cell death or senescence under some conditions [59][60][61][62][63].…”

Section: Hyperactive Ras/raf/mek/erk (Mapk) Signaling In Cancersmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Hyperactive Ras/raf/mek/erk (Mapk) Signaling In Cancersmentioning

confidence: 99%

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

et al. 2020

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“…Multiple studies have suggested a molecular cross-talk between MAPK and Hippo signaling cascades during tumor development. 25 However, the specific biochemical interplay between Yap and MAPK pathways during hepatocarcinogenesis has not been characterized satisfactorily. It would be of high importance to determine the molecular mechanisms whereby YAP, but not TAZ, modulates p-ERK activity in HCC.…”

Section: Discussionmentioning

confidence: 99%

Distinct and Overlapping Roles of Hippo Effectors YAP and TAZ During Human and Mouse Hepatocarcinogenesis

Wang¹,

Wang

Zhang

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims Yes-associated protein (YAP) and its paralog transcriptional co-activator with post synaptic density protein, drosophila disc large tumor suppressor and zonula occludens-1-binding motif (TAZ) are 2 co-activators downstream of Hippo tumor-suppressor cascade. Both have been implicated in the development of hepatocellular carcinoma (HCC). However, whether YAP and TAZ have distinct or overlapping functions during hepatocarcinogenesis remains unknown. Methods Expression patterns of YAP and TAZ were analyzed in human HCC samples. The requirement of Yap and/or Taz in protein kinase B (Akt)/ neuroblastoma RAS viral oncogene homolog (NRas) -driven liver tumorigenesis was analyzed using conditional Yap , Taz , and Yap ; Taz knockout mice. Transcriptional programs regulated by YAP and/or TAZ were identified via RNA sequencing. Results We found that in human HCC samples, an almost ubiquitous activation of YAP or TAZ occurs, underlying their role in this tumor type. Intriguingly, 70% of HCC samples showed only nuclear YAP or TAZ immunoreactivity. In the Akt/NRas liver tumor model, where nuclear Yap and Taz can be detected readily, deletion of Yap or Taz alone only mildly delayed liver tumor development, whereas their concomitant ablation strongly inhibited tumor cell proliferation and significantly suppressed Akt/NRas-driven hepatocarcinogenesis. In HCC cell lines, silencing of either YAP or TAZ led to decreased expression of both overlapping and distinct sets of genes, with the most prominent gene signatures related to cell-cycle progression and DNA replication. Conclusions YAP and TAZ have overlapping and distinct roles in hepatocarcinogenesis. HCCs may display unique activation of YAP or TAZ, thus relying on either YAP or TAZ for their growth.

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“…2A). HIPPO interferes with the RAS and PI3K pathways that control cell death induction [111], acting as a tumor suppressor pathway [112]. Through cross-inhibition, MST and AKT differentially regulate the expression level of pro-apoptotic effectors (NOXA, FASL, BIM, TRAIL).…”

Section: An Altered Hippo Pathway Induces Aerobic Glycolysis In Stsmentioning

confidence: 99%

Metabolic landscapes in sarcomas

et al. 2021

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Metabolic rewiring offers novel therapeutic opportunities in cancer. Until recently, there was scant information regarding soft tissue sarcomas, due to their heterogeneous tissue origin, histological definition and underlying genetic history. Novel large-scale genomic and metabolomics approaches are now helping stratify their physiopathology. In this review, we show how various genetic alterations skew activation pathways and orient metabolic rewiring in sarcomas. We provide an update on the contribution of newly described mechanisms of metabolic regulation. We underscore mechanisms that are relevant to sarcomagenesis or shared with other cancers. We then discuss how diverse metabolic landscapes condition the tumor microenvironment, anti-sarcoma immune responses and prognosis. Finally, we review current attempts to control sarcoma growth using metabolite-targeting drugs.

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Targeting ERK-Hippo Interplay in Cancer Therapy

Cited by 21 publications

References 134 publications

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

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

Distinct and Overlapping Roles of Hippo Effectors YAP and TAZ During Human and Mouse Hepatocarcinogenesis

Metabolic landscapes in sarcomas

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