ArticleAmerican journal of respiratory and critical care medicine2014
Targeting myristoylated alanine-rich C kinase substrate phosphorylation site domain in lung cancer. Mechanisms and therapeutic implications.
Article in American journal of respiratory and critical care medicine, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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45 citing papers in PubMed, 71 citations in OpenAlex.
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- MARCKS Inhibition Alters Bovine Neutrophil Responses toBiomedicines · 2024Article
- The macrophage-associated prognostic gene ANXA5 promotes immunotherapy resistance in gastric cancer through angiogenesis.BMC cancer · 2024Article
- Antitumor effects of chemically modified miR-143 lipoplexes in a mouse model of pelvic colorectal cancer via myristoylated alanine-rich C kinase substrate downregulation.Molecular therapy. Nucleic acids · 2023Article
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- Therapeutic Peptides for Treatment of Lung Diseases: Infection, Fibrosis, and Cancer.International journal of molecular sciences · 2023Review
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- A Novel Renoprotective Strategy: Upregulation of PD-L1 Mitigates Cisplatin-Induced Acute Kidney Injury.International journal of molecular sciences · 2021Article
- The myristoylated alanine-rich C-kinase substrates (MARCKS): A membrane-anchored mediator of the cell function.Autoimmunity reviews · 2021Review
- Targeting the AXL Receptor in Combating Smoking-related Pulmonary Fibrosis.American journal of respiratory cell and molecular biology · 2021Article
- Pathophysiological roles of myristoylated alanine-rich C-kinase substrate (MARCKS) in hematological malignancies.Biomarker research · 2021Review
- Therapeutic targeting of argininosuccinate synthase 1 (ASS1)-deficient pulmonary fibrosis.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- SILAC-Based Quantitative Proteomic Analysis of Oxaliplatin-Resistant Pancreatic Cancer Cells.Cancers · 2021Article
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7 authors at 2 institutions in 1 country.
Funding
Abstract
rationalePhosphorylation of myristoylated alanine-rich C kinase substrate (phospho-MARCKS) at the phosphorylation site domain (PSD) is crucial for mucus granule secretion and cell motility, but little is known concerning its function in lung cancer.
objectivesWe aimed to determine if MARCKS PSD activity can serve as a therapeutic target and to elucidate the molecular basis of this potential.
methodsThe clinical relevance of phospho-MARCKS was first confirmed. Next, we used genetic approaches to verify the functionality and molecular mechanism of phospho-MARCKS. Finally, cancer cells were pharmacologically inhibited for MARCKS activity and subjected to functional bioassays. MEASUREMENTS AND MAIN
resultsWe demonstrated that higher phospho-MARCKS levels were correlated with shorter overall survival of lung cancer patients. Using shRNA silencing and ectopic expression of wild-type and PSD-mutated (S159/163A) MARCKS, we showed that elevated phospho-MARCKS promoted cancer growth and erlotinib resistance. Further studies demonstrated an interaction of phosphoinositide 3-kinase with MARCKS, but not with phospho-MARCKS. Interestingly, phospho-MARCKS acted in parallel with increased phosphatidylinositol (3,4,5)-triphosphate pools and AKT activation in cells. Through treatment with a 25-mer peptide targeting the MARCKS PSD motif (MPS peptide), we were able to suppress tumor growth and metastasis in vivo, and reduced levels of phospho-MARCKS, phosphatidylinositol (3,4,5)-triphosphate, and AKT activity. This peptide also enhanced the sensitivity of lung cancer cells to erlotinib treatment, especially those with sustained activation of phosphoinositide 3-kinase/AKT signaling.
conclusionsThese results suggest a key role for MARCKS PSD in cancer disease and provide a unique strategy for inhibiting the activity of MARCKS PSD as a treatment for lung cancer.
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