ArticleCancer research2023
Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis.
Article in Cancer research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 19 citations in OpenAlex.
- Salvianolic acid monomers against metastasis: Decoding the multilayered interception of EMT, angiogenesis and immune evasion (Review).International journal of molecular medicine · 2026Review
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- Low YTHDC1 Expression Upregulates FSCN1 to Promote Nuclear F-Actin Formation and Facilitate Double-strand DNA Breaks Repair in TMZ-Resistant Glioblastoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Clinical and Functional Characterization of PDE1A as a Wnt/Oncology research · 2026Article
- Autophagy-Related Proteins in Triple-Negative Breast Cancer: From Molecular Insights to Therapeutic Applications.International journal of molecular sciences · 2025Review
- CAMKKβ supports growth and viability of epithelial ovarian cancer in vitro and in vivo.Scientific reports · 2025Article
- Unveiling the multifaceted role of the FLNC gene: implications for cancer diagnosis and prognosis.European journal of medical research · 2025Article
- The role of calcium signaling in organotropic metastasis of cancer.Acta pharmacologica Sinica · 2025Review
- Multifaceted impact of HIV inhibitor dapivirine on triple negative breast cancer cells reveals potential entities as targets for novel therapy.Scientific reports · 2024Article
- PTBP1 mediates Sertoli cell actin cytoskeleton organization by regulating alternative splicing of actin regulators.Nucleic acids research · 2024Article
- Sodium citrate targeting CaJournal of advanced research · 2024Article
- Targeted therapy in high grade serous ovarian Cancer: A literature review.Gynecologic oncology reports · 2024Review
- PTBP1 mediates Sertoli cell actin cytoskeleton organization by regulating alternative splicing of actin regulators.bioRxiv : the preprint server for biology · 2024Article
- EP4-induced mitochondrial localization and cell migration mediated by CALML6 in human oral squamous cell carcinoma.Communications biology · 2024Article
- Salvianolic Acid B Significantly Suppresses the Migration of Melanoma Cells via Direct Interaction with β-Actin.Molecules (Basel, Switzerland) · 2024Article
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- Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies.Biology · 2023Article
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 1 country.
Funding
Abstract
Triple-negative breast cancers (TNBC) tend to become invasive and metastatic at early stages in their development. Despite some treatment successes in early-stage localized TNBC, the rate of distant recurrence remains high, and long-term survival outcomes remain poor. In a search for new therapeutic targets for this disease, we observed that elevated expression of the serine/threonine kinase calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) is highly correlated with tumor invasiveness. In validation studies, genetic disruption of CaMKK2 expression or inhibition of its activity with small molecule inhibitors disrupted spontaneous metastatic outgrowth from primary tumors in murine xenograft models of TNBC. High-grade serous ovarian cancer (HGSOC), a high-risk, poor prognosis ovarian cancer subtype, shares many features with TNBC, and CaMKK2 inhibition effectively blocked metastatic progression in a validated xenograft model of this disease. Mechanistically, CaMKK2 increased the expression of the phosphodiesterase PDE1A, which hydrolyzed cyclic guanosine monophosphate (cGMP) to decrease the cGMP-dependent activity of protein kinase G1 (PKG1). Inhibition of PKG1 resulted in decreased phosphorylation of vasodilator-stimulated phosphoprotein (VASP), which in its hypophosphorylated state binds to and regulates F-actin assembly to facilitate cell movement. Together, these findings establish a targetable CaMKK2-PDE1A-PKG1-VASP signaling pathway that controls cancer cell motility and metastasis by impacting the actin cytoskeleton. Furthermore, it identifies CaMKK2 as a potential therapeutic target that can be exploited to restrict tumor invasiveness in patients diagnosed with early-stage TNBC or localized HGSOC. SIGNIFICANCE: CaMKK2 regulates actin cytoskeletal dynamics to promote tumor invasiveness and can be inhibited to suppress metastasis of breast and ovarian cancer, indicating CaMKK2 inhibition as a therapeutic strategy to arrest disease progression.
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