The CXCR4-LASP1-eIF4F Axis Promotes Translation of Oncogenic Proteins in Triple-Negative Breast Cancer Cells

Triple-negative breast cancer (TNBC) remains clinically challenging as effective targeted therapies are lacking. In addition, patient mortality mainly results from the metastasized lesions. CXCR4 has been identified to be one of the major chemokine receptors involved in breast cancer metastasis. Previously, our lab had identified LIM and SH3 Protein 1 (LASP1) to be a key mediator in CXCR4-driven invasion. To further investigate the role of LASP1 in this process, a proteomic screen was employed and identified a novel protein-protein interaction between LASP1 and components of eukaryotic initiation 4F complex (eIF4F). We hypothesized that activation of the CXCR4-LASP1-eIF4F axis may contribute to the preferential translation of oncogenic mRNAs leading to breast cancer progression and metastasis. To test this hypothesis, we first confirmed that the gene expression of CXCR4, LASP1, and eIF4A are upregulated in invasive breast cancer. Moreover, we demonstrate that LASP1 associated with eIF4A in a CXCL12-dependent manner via a proximity ligation assay. We then confirmed this finding, and the association of LASP1 with eIF4B via co-immunoprecipitation assays. Furthermore, we show that LASP1 can interact with eIF4A and eIF4B through a GST-pulldown approach. Activation of CXCR4 signaling increased the translation of oncoproteins downstream of eIF4A. Interestingly, genetic silencing of LASP1 interrupted the ability of eIF4A to translate oncogenic mRNAs into oncoproteins. This impaired ability of eIF4A was confirmed by a previously established 5′UTR luciferase reporter assay. Finally, lack of LASP1 sensitizes 231S cells to pharmacological inhibition of eIF4A by Rocaglamide A as evident through BIRC5 expression. Overall, our work identified the CXCR4-LASP1 axis to be a novel mediator in oncogenic protein translation. Thus, our axis of study represents a potential target for future TNBC therapies

The CXCR4-LASP1-eIF4F Axis Promotes Translation of Oncogenic Proteins in Triple-Negative Breast Cancer Cells

Triple-negative breast cancer (TNBC) remains clinically challenging as effective targeted therapies are lacking. In addition, patient mortality mainly results from the metastasized lesions. CXCR4 has been identified to be one of the major chemokine receptors involved in breast cancer metastasis. Previously, our lab had identified LIM and SH3 Protein 1 (LASP1) to be a key mediator in CXCR4-driven invasion. To further investigate the role of LASP1 in this process, a proteomic screen was employed and identified a novel protein-protein interaction between LASP1 and components of eukaryotic initiation 4F complex (eIF4F). We hypothesized that activation of the CXCR4-LASP1-eIF4F axis may contribute to the preferential translation of oncogenic mRNAs leading to breast cancer progression and metastasis. To test this hypothesis, we first confirmed that the gene expression of CXCR4, LASP1, and eIF4A are upregulated in invasive breast cancer. Moreover, we demonstrate that LASP1 associated with eIF4A in a CXCL12-dependent manner via a proximity ligation assay. We then confirmed this finding, and the association of LASP1 with eIF4B via co-immunoprecipitation assays. Furthermore, we show that LASP1 can interact with eIF4A and eIF4B through a GST-pulldown approach. Activation of CXCR4 signaling increased the translation of oncoproteins downstream of eIF4A. Interestingly, genetic silencing of LASP1 interrupted the ability of eIF4A to translate oncogenic mRNAs into oncoproteins. This impaired ability of eIF4A was confirmed by a previously established 5'UTR luciferase reporter assay. Finally, lack of LASP1 sensitizes 231S cells to pharmacological inhibition of eIF4A by Rocaglamide A as evident through BIRC5 expression. Overall, our work identified the CXCR4-LASP1 axis to be a novel mediator in oncogenic protein translation. Thus, our axis of study represents a potential target for future TNBC therapies

Continuous, non-invasive techniques to determine cardiac output in children after cardiac surgery: evaluation of transesophageal Doppler and electric velocimetry

BACKGROUND: Continuous and non-invasive measurement of cardiac output (CO) may contribute helpful information to the care and treatment of the critically ill pediatric patient. Different methods are available but their clinical verification is still a major problem. AIM: Comparison of reliability and safety of two continuous non-invasive methods with transthoracic echocardiography (TTE) for CO measurement: electric velocimetry technique (EV, Aesculon) and transesophageal Doppler (TED, CardioQP). METHODS/MATERIAL: In 26 infants and children who had undergone corrective cardiac surgery at a median age of 3.5 (1-17) years CO and stroke volume (SV) were obtained by EV, TED and TTE. Each patient had five measurements on the first day after surgery, during mechanical ventilation and sedation. RESULTS: Values for CO and SV from TED and EV correlated well with those of TTE (r = 0.85 and r = 0.88), but mean values were significantly lower than the values of TTE for TED (P = 0.02) and EV (P = 0.001). According to Bland-Altman analysis, bias was 0.36 l/min with a precision of 1.67 l/min for TED vs. TTE and 0.87 l/min (bias) with a precision of 3.26 l/min for EV vs. TTE. No severe adverse events were observed and the handling of both systems was easy in the sedated child. CONCLUSIONS: In pediatric patients non-invasive measurement of CO and SV with TED and EV is useful for continuous monitoring after heart surgery. Both new methods seem to underestimate cardiac output in terms of absolute values. However, TED shows tolerable bias and precision and may be helpful for continuous CO monitoring in a deeply sedated and ventilated pediatric patient, e.g. in the operating room or intensive care unit