Joseph and Mildred Sonshine Family Center for Head and Neck Diseases

Toronto, Canada

Joseph and Mildred Sonshine Family Center for Head and Neck Diseases

Toronto, Canada
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Matta A.,York University | Michael Siu K.W.,York University | Ralhan R.,York University | Ralhan R.,Joseph and Mildred Sonshine Family Center for Head and Neck Diseases | And 2 more authors.
Expert Opinion on Therapeutic Targets | Year: 2012

Introduction: 14-3-3ζ acts as a central hub in signaling networks, which promotes cell proliferation, adhesion and survival and inhibits apoptosis in multiple cancers. Development of inhibitors or agents that interfere with 14-3-3ζ-dependent signaling networks are likely to serve as novel molecular agents for targeted cancer therapy. Areas covered: The role of 14-3-3ζ in cancer and its potential as a novel molecular target for therapy. The involvement of 14-3-3ζ in chemoresistance in multiple cancers provides a rationale for developing novel molecular therapies targeting this protein for more effective cancer management. The keywords used to conduct the literature search for this paper were '14-3-3/14-3-3zeta and cancer', '14-3-3 structure', '14-3-3 inhibitors', '14-3-3 cancer prognosis', '14-3-3 and cancer therapy', 'role/ functions of 14-3-3'. Expert opinion: 14-3-3ζ is a central cellular hub protein regulating multiple signaling pathways involved in cancer development, progression and therapeutic resistance. Thus, 14-3-3ζ may serve as a novel molecular target for cancer therapy. New approaches including synthetic and/or natural inhibitors that interfere with 14-3-3ζclient interactions need to be developed for effective cancer therapy. © 2012 Informa UK, Ltd.


Matta A.,York University | DeSouza L.V.,York University | Ralhan R.,York University | Ralhan R.,Joseph and Mildred Sonshine Family Center for Head and Neck Diseases | And 3 more authors.
Molecular Cancer Therapeutics | Year: 2010

Patients diagnosed in advanced stages of head and neck squamous cell carcinoma often show limited response to chemotherapeutic agents. Recently, we reported the overexpression of 14-3-3ζ protein in head and neck premalignant and cancer tissues using liquid chromatography-tandem mass spectrometry with isotopic labeling and revealed its significance as a prognostic marker using immunohistochemical analysis. In this study, we determined the potential of 14-3-3ζ as a therapeutic target for head and neck cancer. Small interfering RNA (siRNA) targeting 14-3-3ζ was used to downregulate its expression in head and neck cancer cells in culture. Cell cycle analysis showed that head and neck cancer cells transfected with siRNA targeting 14-3-3ζ showed G2-M arrest. These siRNA transfectants also showed increased cell death on treatment with any one of the following chemotherapeutic agents: cisplatin, 5-fluorouracil, paclitaxel, or doxorubicin in comparison with the no transfection controls. Flow cytometric analysis using propidium iodide staining showed increased sub-G0 fraction in siRNA-transfected cells treated with any of these chemotherapeutic agents, suggesting cell death; in addition, Annexin V staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay revealed increased apoptosis. Taken together, our results strongly showed that downregulation of 14-3-3ζ expression may serve to improve the sensitivity of head and neck cancer cells to chemotherapeutic agents. ©2010 AACR.

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