Calcium/Calmodulin-dependent protein kinase II and its endogenous inhibitor α in medullary thyroid cancer.

Abstract

PURPOSE:

Calcium/calmodulin-dependent kinase II (CaMKII) is involved in the regulation of cell proliferation. Its endogenous inhibitor (hCaKIINα) is expressed in some cell types. We determined the role of CaMKII in RET-stimulated proliferation and hCaMKIINα in medullary thyroid carcinoma (MTC).

EXPERIMENTAL DESIGN:

We analyzed the role of RET mutants on CaMKII activation in NIH3T3 and in MTC cell lines, and determined the effect of CaMKII inhibition on RET/ERK pathway and cell proliferation. Then the expression of hCaKIINα mRNA was determined by real-time PCR in primary MTC and it was correlated with some clinicopathologic parameters.

RESULTS:

RET(C634Y) and RET(M918T) mutants expressed in NIH3T3 cells induced CaMKII activation. CaMKII was activated in unstimulated MTC cells carrying the same RET mutants and it was inhibited by RET inhibition. Inhibition of CaMKII in these cells induced a reduction of Raf-1, MEK, and ERK phosphorylation, cyclin D expression, and cell proliferation. hCaKIINα mRNA expression in primary MTC was very variable and did not correlate with gender and age at diagnosis. Serum calcitonin, (R(2) = 0.032; P = 0.017), tumor volume (P = 0.0079), lymph node metastasis (P = 0.033), and staging (P = 0.0652) were negatively correlated with the hCaKIINα mRNA expression.

CONCLUSIONS:

CaMKII is activated by RET mutants and is activated at baseline in MTC cells where it mediates the oncogenic pathway leading to cell proliferation. The mRNA expression of its endogenous inhibitor hCaKIINα inversely correlates with the severity of MTC. CaMKII might represent a new target for MTC therapy and hCaKIINα is a marker of disease extension.

• Authors: Eleonora Russo, Marcella Salzano, Valentina De Falco, Caterina Mian, Susi Barollo, Agnese Secondo, Maurizio Bifulco, Mario Vitale
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 6 Pg. 1513-20 (Mar 15 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24449826 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 AACR.

Chemical References

• CAMK2N1 protein, human
• Proteins
• Proto-Oncogene Proteins c-ret
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Blotting, Western
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism)
• Carcinoma, Neuroendocrine
• Cell Proliferation
• Female
• Humans
• Male
• Mice
• Middle Aged
• Mutation
• NIH 3T3 Cells
• Proteins (metabolism)
• Proto-Oncogene Proteins c-ret (genetics)
• Real-Time Polymerase Chain Reaction
• Signal Transduction (physiology)
• Thyroid Neoplasms (enzymology)