Dysregulation of the tightly controlled protein phosphorylation networks that govern cellular behavior causes cancer. The membrane-associated, intracellular protein tyrosine phosphatase PTP4A3 is overexpressed in human colorectal cancer and contributes to cell migration and invasion. To interrogate further the role of PTP4A3 in colorectal cancer cell migration and invasion, we deleted the Ptp4a3 gene from murine colorectal tumor cells. The resulting PTP4A3 cells exhibited impaired colony formation, spheroid formation, migration, and adherence compared with the paired PTP4A3 cells. We replicated these phenotypic changes using the new small-molecule, allosteric PTP4A3 inhibitor JMS-053. A related structure, JMS-038, which lacked phosphatase inhibition, displayed no cellular activity. Reduction in cell viability and colony formation by JMS-053 occurred in both mouse and human colorectal cell lines and required PTP4A3 expression. Ptp4a3 deletion increased the expression of extracellular matrix (ECM) and adhesion genes, including the tumor suppressor Emilin 1. JMS-053 also increased Emilin 1 gene expression. Moreover, The Cancer Genome Atlas genomic database revealed human colorectal tumors with high Ptp4a3 expression had low Emilin 1 expression. These chemical and biologic reagents reveal a previously unknown communication between the intracellular PTP4A3 phosphatase and the ECM and support efforts to pharmacologically target PTP4A3.-McQueeney, K. E., Salamoun, J. M., Ahn J. G., Pekic, P., Blanco, I. K., Struckman, H. L., Sharlow, E. R., Wipf, P., Lazo, J. S. A chemical genetics approach identifies PTP4A3 as a regulator of colon cancer cell adhesion.

Risk of suicidality during smoking cessation treatment is an important, but often overlooked, aspect of nicotine addiction research and treatment. We explore the relationship between smoking cessation interventions and suicidality and explore common treatments, their associated risks, and effectiveness in promoting smoking reduction and abstinence. Although active smokers have been reported to have twofold to threefold increased risk of suicidality when compared to nonsmokers,1–4 research regarding the safest way to stop smoking does not always provide clear guidelines for practitioners wishing to advise their patients regarding smoking cessation strategies. In this article, we review pharmacological and cognitive behavioral therapy (CBT) options that are available for people seeking to quit smoking, focusing on the relationship between the ability of these therapies to reduce smoking behavior and promote abstinence and suicidality risks as assessed by reported suicidality on validated measures, reports of suicidal ideation, behaviors, actual attempts, or completed suicides. Pharmacotherapies such as varenicline, bupropion, and nicotine replacement, and CBTs, including contextual CBT interventions, have been found to help reduce smoking rates and promote and maintain abstinence. Suicidality risks, while present when trying to quit smoking, do not appear to demonstrate a consistent or significant rise associated with use of any particular smoking cessation pharmacotherapy or CBT/contextual CBT intervention reviewed.

Dysregulation of the tightly controlled protein phosphorylation networks that govern cellular behavior causes cancer. The membrane-associated, intracellular protein tyrosine phosphatase PTP4A3 is overexpressed in human colorectal cancer and contributes to cell migration and invasion. To interrogate further the role of PTP4A3 in colorectal cancer cell migration and invasion, we deleted the Ptp4a3 gene from murine colorectal tumor cells. The resulting PTP4A3-/- cells exhibited impaired colony formation, spheroid formation, migration, and adherence compared to the isogenic PTP4A3fl/fl cells. We replicated these phenotypic changes using the new small molecule allosteric PTP4A3 inhibitor, JMS-053. A related structure, JMS-038, which lacked phosphatase inhibition, displayed no cellular activity. Reduction in cell viability and colony formation by JMS-053 occurred in both mouse and human colorectal cell lines and required PTP4A3 expression. Ptp4a3 deletion increased the expression of extracellular matrix and adhesion genes, including the tumor suppressor Emilin 1. JMS-053 also increased Emilin 1 gene expression. Moreover, the human TCGA genomic database revealed colorectal tumors with high Ptp4a3 expression had low Emilin1 expression. These chemical and biological reagents reveal a previously unknown communication between the intracellular PTP4A3 phosphatase and the extracellular matrix and support efforts to pharmacologically target PTP4A3. Citation Format: Kelley E. McQueeney, Joseph M. Salamoun, Jennifer Ahn, Paula Pekic, Isabella K. Blanco, Heather Struckman, Elizabeth R. Sharlow, Peter Wipf, John S. Lazo. A chemical genetics approach identifies PTP4A3 as a regulator of colon cancer cell adhesion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2365.

Aberrant regulation of protein phosphorylation is an exceedingly common driver of human cancers. It is notable that we understand much less about the role of protein tyrosine phosphatases in human malignancies compared to tyrosine kinases. The membrane-associated, intracellular, protein tyrosine PTP4A3 is highly overexpressed in multiple tumor types including colorectal cancer and has been associated with tumor metastases. We have, therefore, investigated the role of PTP4A3 in colon cancer migration and invasion. The Ptp4a3 gene was expunged from colon tumor cells derived from Ptp4a3flox/flox mice and the resulting cells exhibited impaired migration, invasion, and colony formation compared to the wildtype isogenic cells. We characterized a potent, selective, and noncompetitive small molecule inhibitor of PTP4A3, JMS-631-053, which also disrupted colon cancer cell migration, invasion, and colony formation. PTP4A3 deletion increased the expression of extracellular matrix and adhesion genes, including the tumor suppressor Emilin 1. Expression of these extracellular matrix genes is mutually exclusive with PTP4A3 expression in tumors derived from patients with colorectal cancer. These chemical and biological reagents reveal a previously unknown communication between the intracellular PTP4A3 phosphatase and the extracellular matrix and support continued efforts to pharmacologically target PTP4A3 for cancer therapy. Citation Format: Kelley E. McQueeney, Joseph M. Salamoun, Isabella K. Blanco, Paula Pekic, Jennifer Ahn, Elizabeth R. Sharlow, Peter Wipf, John S. Lazo. Coordinated chemical-genetics approach identifies PTP4A3-mediated regulation of colon cancer cell migration and extracellular matrix interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1220. doi:10.1158/1538-7445.AM2017-1220

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States and the world and the 5-year survival rate in the United States of ∼60% highlights the need for better treatment options. The central challenge in the design and development of drugs to treat CRC has been the validation of novel drug targets and the generation of new therapies aimed at those targets. The goal of this project is to better understand the role of one such potential CRC molecular target. Protein Tyrosine Phosphatase 4A3 (PTP4A3) is currently among the most consistently up-regulated proteins seen in colorectal tumors but it suffers from an incomplete understanding of its substrate(s) and of its participation in tumor formation and progression. To clarify how PTP4A3 expression impacts cell behavior, we isolated primary colon tumor epithelial cells from Ptp4a3fl/fl mice. PTP4A3 was deleted in vitro by adenoviral infection of Ptp4a3fl/fl cells with Cre recombinase accompanied by a green fluorescent protein (GFP) marker. As a control, the Ptp4a3fl/fl cells were infected with GFP alone. Virally infected cells were selected by fluorescence activated cell sorting. In the sorted cells, the expression of Cre resulted in a complete lack of PTP4A3 protein by western blotting and undetectable Ptp4a3 mRNA as determine by quantitative RT-PCR. Analysis of these genetically similar cells revealed that Ptp4a3−/− tumor cells had significantly reduced colony formation and migration as compared to Ptp4a3fl/fl cells. Notably, the growth rate of Ptp4a3fl/fl and Ptp4a3−/− cells was similar when cultured on plastic in a 2D monolayer. In contrast, Ptp4a3fl/fl spheroids grew significantly faster than the Ptp4a3−/− cells when cultured in Matrigel. Moreover, while the Ptp4a3fl/fl cells were able to form cohesive spheroids when cultured in cell repellent plates, there was a striking inability of the Ptp4a3−/− cells to form these 3D structures. In addition, treatment of the Ptp4a3fl/fl cells with a potent and selective PTP4A3 phosphatase inhibitor, thienopyridone, phenocopied the appearance of the Ptp4a3−/− cells grown in cell repellent plates. These results suggest PTP4A3 expression-dependent changes in tumor cell behavior may be rooted in a disruption in the adhesion and extracellular matrix-signaling axis. This hypothesis was supported by significant changes in the gene expression profile of adhesion and extracellular matrix proteins in the Ptp4a3−/− CRC cells. The isogenic Ptp4a3fl/fl and Ptp4a3−/− CRC cells provide an invaluable tool to elucidate further the function of PTP4A3 and its link to adhesion and the extracellular matrix interactions. Citation Format: Kelley E. McQueeney, Paula Pekic, Joseph M. Salamoun, Jennifer Ahn, Elizabeth R. Sharlow, Peter Wipf, John S. Lazo. Depletion of PTP4A3 phosphatase disrupts colorectal cancer cell adhesion and extracellular matrix interactions. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 202.