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  • Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis.

Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis.

Cancer research (2023-06-19)
Debarati Mukherjee, Rebecca A Previs, Corinne Haines, Muthana Al Abo, Patrick K Juras, Kyle C Strickland, Binita Chakraborty, Sandeep Artham, Regina S Whitaker, Katherine Hebert, Jake Fontenot, Steven R Patierno, Jennifer A Freedman, Frank H Lau, Matthew E Burow, Ching-Yi Chang, Donald P McDonnell
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. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-CAMKK2 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Nω-Nitro-L-arginine, ≥98% (TLC)
Sigma-Aldrich
Anti-phospho-VASP (Ser239) Antibody, clone 16C2, clone 16C2, Upstate®, from mouse
Sigma-Aldrich
KT 5823, ≥85% (HPLC), lyophilized powder
Sigma-Aldrich
Nω-Nitro-L-arginine methyl ester hydrochloride, ≥97% (TLC), powder
Sigma-Aldrich
PKG Inhibitor, The PKG Inhibitor controls the biological activity of PKG. This small molecule/inhibitor is primarily used for Phosphorylation & Dephosphorylation applications.