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BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

Targeting cell migration and the endoplasmic reticulum stress response with calmodulin antagonists: a clinically tested small molecule phenocopy of SEC62 gene silencing in human tumor cells

Authors: Maximilian Linxweiler, Stefan Schorr, Nico Schäuble, Martin Jung, Johannes Linxweiler, Frank Langer, Hans-Joachim Schäfers, Adolfo Cavalié, Richard Zimmermann, Markus Greiner

Published in: BMC Cancer | Issue 1/2013

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Abstract

Background

Tumor cells benefit from their ability to avoid apoptosis and invade other tissues. The endoplasmic reticulum (ER) membrane protein Sec62 is a key player in these processes. Sec62 is essential for cell migration and protects tumor cells against thapsigargin-induced ER stress, which are both linked to cytosolic Ca2+. SEC62 silencing leads to elevated cytosolic Ca2+ and increased ER Ca2+ leakage after thapsigargin treatment. Sec62 protein levels are significantly increased in different tumors, including prostate, lung and thyroid cancer.

Methods

In lung cancer, the influence of Sec62 protein levels on patient survival was analyzed using the Kaplan-Meier method and log-rank test. To elucidate the underlying pathophysiological functions of Sec62, Ca2+ imaging techniques, real-time cell analysis and cell migration assays were performed. The effects of treatment with the calmodulin antagonists, trifluoperazine (TFP) and ophiobolin A, on cellular Ca2+ homeostasis, cell growth and cell migration were compared with the effects of siRNA-mediated Sec62 depletion or the expression of a mutated SEC62 variant in vitro. Using Biacore analysis we examined the Ca2+-sensitive interaction of Sec62 with the Sec61 complex.

Results

Sec62 overproduction significantly correlated with reduced patient survival. Therefore, Sec62 is not only a predictive marker for this type of tumor, but also an interesting therapeutic target. The present study suggests a regulatory function for Sec62 in the major Ca2+ leakage channel in the ER, Sec61, by a direct and Ca2+-sensitive interaction. A Ca2+-binding motif in Sec62 is essential for its molecular function. Treatment of cells with calmodulin antagonists mimicked Sec62 depletion by inhibiting cell migration and rendering the cells sensitive to thapsigargin treatment.

Conclusions

Targeting tumors that overproduce Sec62 with calmodulin antagonists in combination with targeted thapsigargin analogues may offer novel personalized therapeutic options.
Appendix
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Metadata
Title
Targeting cell migration and the endoplasmic reticulum stress response with calmodulin antagonists: a clinically tested small molecule phenocopy of SEC62 gene silencing in human tumor cells
Authors
Maximilian Linxweiler
Stefan Schorr
Nico Schäuble
Martin Jung
Johannes Linxweiler
Frank Langer
Hans-Joachim Schäfers
Adolfo Cavalié
Richard Zimmermann
Markus Greiner
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-574

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