Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma

Haak, Andrew J.; Appleton, Kathryn M.; Lisabeth, Erika M.; Misek, Sean A.; Ji, Yajing; Wade, Susan M.; Bell, Jessica L.; Rockwell, Cheryl E.; Airik, Merlin; Krook, Melanie A.; Larsen, Scott D.; Verhaegen, Monique; Lawlor, Elizabeth R.; Neubig, Richard R.

doi:10.1158/1535-7163.mct-16-0482

Cited by 38 publications

(58 citation statements)

References 49 publications

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“…As previously reported (20) for a structurally similar compound, CCG-203971, CCG-222740 effectively reduced MRTF-A nuclear localization in a concentration dependent manner in SK-Mel-147 cells (Fig. 4A-B).…”

Section: Ccg-222740 Disrupts Nuclear Localization Of Mrtf-a and Mrtf-supporting

confidence: 86%

“…Our recent findings indicated a role of the Rho/MRTF pathway in migration, invasion and metastasis of aggressive human cutaneous melanoma (20,34), as well as in the acquired resistance of BRAF mutant melanoma cells to BRAF inhibitors (34). Therefore, we hypothesized that the Rho/MRTF pathway might play a role in the intrinsic resistance of some of the NRAS mutant melanoma cells to trametinib-induced inhibition of cell viability.…”

Section: Mrtf Pathway Activation Correlates With Trametinib Resistancementioning

confidence: 97%

“…In cutaneous melanoma patients, increased expression of RhoC or MRTF-A mRNA has been linked to overall poor patient survival (20). Myocardin-related transcription factor (MRTF) is a pair (MRTF-A and -B) of transcription cofactors downstream of Rho GTPases (21,22).…”

Section: Introductionmentioning

confidence: 99%

“…Depletion of MRTF via RNA interference (RNAi) in the highly metastatic B16F2 melanoma cell line reduced in vitro cell migration and in vivo lung metastasis (26). Additionally, pharmacologic inhibition of the Rho/MRTF-pathway by the small-molecule CCG-203971 significantly reduced in vitro cellular migration and invasion (20,28), as well as in vivo lung metastasis in the RhoC-expressing NRAS mutant melanoma cell line SK-Mel-147 (20). In addition to its anti-migratory and anti-metastatic properties, CCG-203971 induced G1-cell cycle arrest in melanoma cells.…”

Section: Introductionmentioning

confidence: 99%

“…Here, we show that a panel of four NRAS Q61 mutant melanoma cell lines had varying sensitivity to trametinib treatment and that the Rho/MRTF pathway was activated in the subset of NRAS mutant melanoma cell lines with high intrinsic resistance to trametinib-mediated cell growth inhibition.Amplification of RhoA/C or MKL1/2 (gene names for MRTF-A/B) or mutations in upstream activators of RhoA/C have been found in ~30% cutaneous melanomas. Increased expression of RhoC or MRTF-A has been linked to aggressive disease and overall poor patient survival(20).While the MRTF-SRF transcriptional axis plays a pro-metastatic role in cancers, the Rho/MRTF pathway is also emerging as a drug resistance mechanism in different types of skinmalignancies. Whitson et al reported that activation of the Rho/MRTF pathway promoted resistance to a smoothened (SMO) inhibitor in basal cell carcinoma (BCC) (41).…”

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confidence: 99%

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Inhibition of the Myocardin-Related Transcription Factor pathway increases efficacy of Trametinib in NRAS-mutant melanoma cell lines

Appleton

Palsuledesai

Misek

et al. 2019

Preprint

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The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (~50% BRAF V600 mutations and ~30% NRAS mutations). While targeted therapies have yielded success in BRAF V600 mutant melanoma patients, such therapies have been ineffective in NRAS mutant melanomas in part due to their cytostatic effects and primary resistance in this patient population. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines. Combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells which have a high level of trametinib resistance. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlights the potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas.

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Section: Ccg-222740 Disrupts Nuclear Localization Of Mrtf-a and Mrtf-supporting

confidence: 86%

Section: Mrtf Pathway Activation Correlates With Trametinib Resistancementioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of the Myocardin-Related Transcription Factor pathway increases efficacy of Trametinib in NRAS-mutant melanoma cell lines

Appleton

Palsuledesai

Misek

et al. 2019

Preprint

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Optogenetic Control of Myocardin‐Related Transcription Factor A Subcellular Localization and Transcriptional Activity Steers Membrane Blebbing and Invasive Cancer Cell Motility

Zhao

Grosse

2021

Advanced Biology

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Similar to SRF, its coactivator MRTF-A (also known as MAL or MKL1) is ubiquitously expressed and controls actin-associated gene expression for numerous functions in development and disease as well as many cell migratory processes. [3,4] The latter occurs largely via the regulation of cytoskeletal genes following signal-induced MRTF-A nuclear translocation. [5][6][7] Notably, MRTF-A dependent immediate gene expression appears to be the predominant cellular SRF transcriptional response to extracellular signals such as serum. [8] In addition, it is now well established that MRTF-A transcriptional activity is an important driver of tumor progression by promoting invasion and metastasis. [9][10][11][12][13][14][15][16] We could recently show that MRTF-A activity promotes non-apoptotic plasma membrane (PM) blebbing often observed during blebassociated invasive cell migration. [17] This MRTF-A nuclear activity was in turn triggered by PM blebbing thereby facilitating a positive feedback loop to drive PM dynamics and cell motility through MRTF-SRF transcription. [17] Such mechanism is consistent with the fact that nuclear localization of MRTF-A depends on actin dynamics. [5] This occurs via three core RPEL actin-binding sites (R1-R3) and the two spacer actin-binding regions (S1, S2) within the N-terminus of MRTF-A (Figure 1A). [18] Specifically, the RPEL domain of MRTF-A interacts with actin such that binding of all five actin monomers (G-actin) promotes MRTF-A nuclear export while dissociation of the G-actin molecules favors its Nuclear localization signal (NLS)-dependent nuclear import (Figure 1A). [18] This mechanism allows MRTF-A to sense and rapidly respond to changes in actin dynamics resulting in the regulation of gene expression. [19] Nucleocytoplasmic shuttling is regarded as an essential mechanism to control the activity of transcriptional factors. [20] Quite recently, a few optogenetic tools have been generated to artificially manipulate the localization of nuclear proteins, [21] providing a new perspective for modulating cellular activities. Here, we devised and employed an optogenetic strategy using the modified light-oxygen-voltage-sensing domain 2 (LOV2) LEXY to spatiotemporally control MRTF-A nuclear localization and function independently of actin dynamics. Optogenetic The myocardin-related transcription factor A (MRTF-A) controls the transcriptional activity of the serum response factor (SRF) in a tightly controlled actin-dependent manner. In turn, MRTF-A is crucial for many actin-dependent processes including adhesion, migration, and contractility and has emerged as a novel target for anti-tumor strategies. MRTF-A rapidly shuttles between cytoplasmic and nuclear compartment via dynamic actin interactions within its N-terminal RPEL domain.Here, optogenetics is used to spatiotemporally control MRTF-A nuclear localization by blue light using the light-oxygen-voltage-sensing domain 2-domain based system LEXY (light-inducible nuclear export system). It is found that lightregulated nuclear export of MRTF-A o...

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MRTFs‐ master regulators of EMT

Gasparics

Sebe

2017

Developmental Dynamics

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Recent evidence implicates the myocardin-related transcription factors (MRTFs) as key mediators of the phenotypic plasticity leading to the conversion of various cell types into myofibroblasts. This review highlights the function of MRTFs during development, fibrosis and cancer, and the role of MRTFs during epithelial-mesenchymal transitions (EMTs) underlying these processes. EMT is a sequentially orchestrated process where cells undergo a rearrangement of their cell contacts and activate a fibrogenic and myogenic expression program. MRTFs interact with and regulate the major signaling pathways and the expression of key markers and transcription factors involved in EMT. These functions indicate a central role for MRTFs in controlling the process of EMT. Developmental Dynamics 247:396-404,

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Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma

Cited by 38 publications

References 49 publications

Inhibition of the Myocardin-Related Transcription Factor pathway increases efficacy of Trametinib in NRAS-mutant melanoma cell lines

Inhibition of the Myocardin-Related Transcription Factor pathway increases efficacy of Trametinib in NRAS-mutant melanoma cell lines

Optogenetic Control of Myocardin‐Related Transcription Factor A Subcellular Localization and Transcriptional Activity Steers Membrane Blebbing and Invasive Cancer Cell Motility

MRTFs‐ master regulators of EMT

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