The interactome and spatial redistribution feature of Ca2+ receptor protein calmodulin reveals a novel role in invadopodia-mediated invasion.

Abstract

Numerous studies have shown that calmodulin (CaM) is a major regulator of calcium-dependent signaling, which regulates cell proliferation, programmed cell death, and autophagy in cancer. However, limited information is available on mechanisms underlying the effect of CaM on the invasive property of glioblastoma multiforme (GBM) cells, especially with respect to invadopodia formation. In this study, we find that CaM serves as a prognostic factor for GBM, and it is strongly associated with the invasive nature of this tumor. Results of preliminary experiments indicated that CaM concentration was significantly correlated with the invasive capacity of and invadopodia formation by different GBM cell lines. CaM inhibition via a small hairpin RNA or a pharmacological inhibitor significantly disrupted invadopodia formation and MMP activity and downregulated vimentin expression. Moreover, CaM knockdown exerted a strong anti-invasive effect on GBM in vivo. Interestingly, epidermal growth factor treatment promoted CaM redistribution from the nucleus to the cytoplasm, eventually activating invadopodia-associated proteins by binding to them via their cytosolic-binding sites. Moreover, CaM inhibition suppressed the activation of invadopodia-associated proteins. Thus, our findings provide a novel therapeutic strategy to impede GBM invasion by inhibiting invadopodia formation, and shed light on the spatial organization of CaM signals during GBM invasion.

• Authors: Tao Li, Li Yi, Long Hai, Haiwen Ma, Zhennan Tao, Chen Zhang, Iruni Roshanie Abeysekera, Kai Zhao, Yihan Yang, Wei Wang, Bo Liu, Shengping Yu, Luqing Tong, Peidong Liu, Meng Zhu, Bingcheng Ren, Yu Lin, Kai Zhang, Cheng Cheng, Yubao Huang, Xuejun Yang
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 3 Pg. 292 (02 20 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 29463791 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calmodulin
• RNA, Small Interfering
• Vimentin
• Epidermal Growth Factor
• Calcium

Topics

• Brain Neoplasms (genetics, metabolism, pathology)
• Calcium (metabolism)
• Calmodulin (genetics, metabolism)
• Cell Line, Tumor
• Epidermal Growth Factor (metabolism)
• Glioblastoma (genetics, metabolism, pathology)
• Humans
• Neoplasm Invasiveness
• Podosomes (metabolism)
• Protein Transport
• RNA, Small Interfering (genetics, metabolism)
• Vimentin (genetics, metabolism)