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ERK activation and cell growth require CaM kinases in MCF-7 breast cancer cells

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Abstract

Previous studies on MCF-7 breast cancer cells have shown that the G-protein coupled receptor (GPCR) agonist carbachol increases intracellular calcium levels and the activation of extracellular signal-regulated kinase (ERK). Calcium and calmodulin regulate the calcium/calmodulin-dependent kinase (CaM kinase) family of proteins that have been proposed to regulate ERK and gene transcription. Our results suggest that both estrogen (E2) and carbachol treatment of MCF-7 breast cancer cells trigger phosphorylation of ERK1/2 and the transcription factor Elk-1. Carbachol and estrogen triggered nearly a four- to sixfold increase in MCF-7 cell proliferation by 96 h, respectively. Carbachol-stimulated ERK activation and cell growth was completely blocked by the Muscarinic M3-subtype GPCR inhibitor, 4-DAMP, and siRNA against the M3-subtype GPCR. Interestingly, blockade of CaM KK with the selective inhibitor STO-609 prevented carbachol activation CaM KI, ERK, Elk-1, and cell growth. Consistent with these observations, knockdown of CaM KKα and CaM KIγ with shRNA-containing plasmids blocked ERK activation by carbachol. In addition, Elk-1 phosphorylation and luciferase activity in response to carbachol treatment was also dependent upon CaM kinases and was inhibited by U0126, STO-609, and siRNA knockdown of CaM kinases and ERK2. Finally, blockade of either CaM KK (with STO-609) or ERK (with U0126) activities resulted in the inhibition of carbachol- and estrogen-mediated cyclin D1 expression and MCF-7 cell growth. Taken together, our results suggest that carbachol treatment of MCF-7 cells activates CaM KI, ERK, the transcription factor Elk-1, cyclin D1, and cell growth through CaM KK.

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Abbreviations

MAPK:

Mitogen-activated protein kinase

ERK:

Extracellular signal-regulated kinase

CaM:

Calmodulin

AKT:

Protein kinase B

EGF:

Epidermal growth factor

β-Estradiol:

Estrogen (E2)

CaM kinase:

Calcium/calmodulin-dependent protein kinase

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Acknowledgments

The authors would like to thank Tom Soderling for providing reagents and helpful discussions and Luke Fletcher as well as Sean Nygaard for technical assistance. This work was supported in part by the Paul K. and Evalyn E. C. Richter Memorial Fund and the Holman Endowment for the Sciences at George Fox University to Andrea Wagner and Ellen Abell.

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  1. The Biology Department, George Fox University, 414 N. Meridian St, Newberg, OR, 97132, USA

    John M. Schmitt, Ellen Abell & Andrea Wagner

  2. Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239, USA

    Monika A. Davare

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  1. John M. Schmitt
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Correspondence to John M. Schmitt.

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Schmitt, J.M., Abell, E., Wagner, A. et al. ERK activation and cell growth require CaM kinases in MCF-7 breast cancer cells. Mol Cell Biochem 335, 155–171 (2010). https://doi.org/10.1007/s11010-009-0252-9

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