The Role of MARCKS in Metastasis and Treatment Resistance of Solid Tumors

Chiu, Chun-Lung; Zhao, Hongjuan; Chen, Ching-Hsien; Wu, Reen; Brooks, James D.

doi:10.3390/cancers14194925

Cited by 8 publications

(5 citation statements)

References 83 publications

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“…While our report newly demonstrates that one of the major effect of NMT1 KO and PCLX-001 treatment is on mitochondrial proteins, we showed that NMT inhibition also profoundly affected numerous myristoylated signaling proteins in addition to SFKs, including oncogenes (ABL2 [ 66 ], MARCKS [ 67 ], BASP1 [ 68 ]), membrane lipid raft proteins including flotillin-2 [ 69 ] and raftlin [ 70 ], and proteins involved in vesicular transport (e.g., Arf1-6) [ 71 ] (Fig. 4 ).…”

Section: Discussionmentioning

confidence: 83%

Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition

Beauchamp,

Gamma,

Cromwell

et al. 2024

J Transl Med

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Background In humans, two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numerous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective killing of these cells, sparing normal cells with both NMTs. Methods and results Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes. Conclusions Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.

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Section: Discussionmentioning

confidence: 83%

Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition

Beauchamp,

Gamma,

Cromwell

et al. 2024

J Transl Med

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“…As previously reported, MARCKS translocation was correlated with either PKC/RhoA-dependent PSD phosphorylation or calcium-dependent calmodulin binding [ 38 ], and we further analyzed the results shown in Fig. 6 A to filter potential proteins related to MARCKS translocation.…”

Section: Resultsmentioning

confidence: 93%

“…For instance, Wenzel T et al reported that CRC cells lacking MARCKS expression exhibit enhanced chemoresistance due to increased ABCB1 expression [ 58 ]; moreover, MARCKS protein expression levels are inversely correlated with GBM proliferation and intracranial xenograft growth rates in vivo [ 59 ]. In addition, the oncogenic roles of MARCKS in cancer proliferation, metastasis and chemoresistance have also been demonstrated [ 38 ]. The roles of MARCKS are strongly correlated with its subcellular location in cells, as membrane-located MARCKS interacts with PI [ 4 , 5 ]P 2 ; once MARCKS is translocated into the cytoplasm, PI [ 4 , 5 ]P 2 is released from MARCKS to further interact with other proteins and activate downstream pathways, such as the PI3K/AKT/mTOR pathway [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

CircTRIM1 encodes TRIM1-269aa to promote chemoresistance and metastasis of TNBC via enhancing CaM-dependent MARCKS translocation and PI3K/AKT/mTOR activation

Li,

Wang,

Yang

et al. 2024

Mol Cancer

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Peptides and proteins encoded by noncanonical open reading frames (ORFs) of circRNAs have recently been recognized to play important roles in disease progression, but the biological functions and mechanisms of these peptides and proteins are largely unknown. Here, we identified a potential coding circular RNA, circTRIM1, that was upregulated in doxorubicin-resistant TNBC cells by intersecting transcriptome and translatome RNA-seq data, and its expression was correlated with clinicopathological characteristics and poor prognosis in patients with TNBC. CircTRIM1 possesses a functional IRES element along with an 810 nt ORF that can be translated into a novel endogenously expressed protein termed TRIM1-269aa. Functionally, we demonstrated that TRIM1-269aa, which is involved in the biological functions of circTRIM1, promoted chemoresistance and metastasis in TNBC cells both in vitro and in vivo. In addition, we found that TRIM1-269aa can be packaged into exosomes and transmitted between TNBC cells. Mechanistically, TRIM1-269aa enhanced the interaction between MARCKS and calmodulin, thus promoting the calmodulin-dependent translocation of MARCKS, which further initiated the activation of the PI3K/AKT/mTOR pathway. Overall, circTRIM1, which encodes TRIM1-269aa, promoted TNBC chemoresistance and metastasis by enhancing MARCKS translocation and PI3K/AKT/mTOR activation. Our investigation has yielded novel insights into the roles of protein-coding circRNAs and supported circTRIM1/TRIM1-269aa as a novel promising prognostic and therapeutic target for patients with TNBC.

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“…105 Additionally, we have observed an elevation in myristoylated alanine-rich C-kinase substrate (MARCKS), which facilitates cancer metastasis through modulating cancer cell migration and invasion, in cells on collagen IV-coated surfaces. 106 We further treated cells with selective inhibitors of AXL (XL184 and R428) and the treatments successfully reduced cell motility on collagen IV but not collagen I (Fig. 8B and C).…”

Section: Lab On a Chip Papermentioning

confidence: 95%

Microfluidic single-cell migration chip reveals insights into the impact of extracellular matrices on cell movement

Zhou,

Ma,

Rock

et al. 2023

Lab Chip

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The Role of MARCKS in Metastasis and Treatment Resistance of Solid Tumors

Cited by 8 publications

References 83 publications

Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition

Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition

CircTRIM1 encodes TRIM1-269aa to promote chemoresistance and metastasis of TNBC via enhancing CaM-dependent MARCKS translocation and PI3K/AKT/mTOR activation

Microfluidic single-cell migration chip reveals insights into the impact of extracellular matrices on cell movement

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