Abstract
BackgroundTumor 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.MethodsIn 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.ResultsSec62 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.ConclusionsTargeting tumors that overproduce Sec62 with calmodulin antagonists in combination with targeted thapsigargin analogues may offer novel personalized therapeutic options.
Highlights
Tumor cells benefit from their ability to avoid apoptosis and invade other tissues
Sec62 levels in cancer tissue predicts survival of non-small cell lung cancer (NSCLC) patients In our previous study, we detected SEC62 amplification and overexpression in NSCLC that did not correlate with patient age or sex but, at least for squamous cell carcinoma (SCC), correlated with the appearance of lymph node metastases and the grade of differentiation [5]
The clinical relevance of the Sec62 protein level for SCC of the lung is even more important given that the increased Sec62 protein level protects tumor cells from thapsigargin therapy [13]
Summary
Tumor cells benefit from their ability to avoid apoptosis and invade other tissues. The endoplasmic reticulum (ER) membrane protein Sec is a key player in these processes. Elevated Sec protein levels are functionally linked to increased cell migration capability [12] and reduced sensitivity to thapsigargin-induced ER stress [13], both of which are tightly regulated by the cytosolic Ca2+ concentration [14,15,16]. We have shown that reduced Sec protein levels lead to an at least two-fold increase in basal cytosolic Ca2+ and a much greater increase in cytosolic Ca2+ concentration in response to thapsigargin treatment (i.e., increased ER Ca2+ leakage) [13] These results demonstrate a significant influence of Sec on ER Ca2+ homeostasis, making Sec a promising target for new therapeutic approaches. Regulation of cytosolic Ca2+ levels by targeting this protein may induce anti-metastatic and anti-proliferative effects
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