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Ralhan R.,York University | Ralhan R.,Joseph and Mildred Sonshine Family Center for Head and Neck Diseases | Ralhan R.,Alex and Simona Shnaider Research Laboratory in Molecular Oncology | Ralhan R.,University of Toronto | And 5 more authors.
Proteomics | Year: 2011

In search of blood-based biomarkers that would enhance the ability to diagnose head and neck/oral squamous cell carcinoma (HNOSCC) in early stages or predict its prognosis, we analyzed the HNOSCC secretome (ensemble of proteins secreted and/or shed from the tumor cells) for potential biomarkers using proteomic technologies. LC-MS/MS was used to identify proteins in the conditioned media of four HNOSCC cell lines (SCC4, HSC2, SCC38, and AMOSIII); 140 unique proteins were identified on the basis of 5% global false discovery rate, 122 of which were secretory proteins, with 29 being previously reported to be overexpressed in HNOSCC in comparison to normal head and neck tissues. Of these, five proteins including α-enolase, peptidyl prolyl isomerase A/cyclophilin A, 14-3-3 ζ, heterogeneous ribonucleoprotein K, and 14-3-3 σ were detected in the sera of HNOSCC patients by Western blot analysis. Our study provides the evidence that analysis of head and neck cancer cells' secretome is a viable strategy for identifying candidate serological biomarkers for HNOSCC. In future, these biomarkers may be useful in predicting the likelihood of transformation of oral pre-malignant lesions, prognosis of HNOSCC patients and evaluate response to therapy using minimally invasive tests. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

Macha M.A.,All India Institute of Medical Sciences | Matta A.,York University | Chauhan S.S.,All India Institute of Medical Sciences | Michael Siu K.W.,York University | And 4 more authors.
Carcinogenesis | Year: 2011

Understanding the molecular pathways perturbed in smokeless tobacco- (ST) associated head and neck squamous cell carcinoma (HNSCC) is critical for identifying novel complementary agents for effective disease management. Activation of nuclear factorkappaB (NF-kB) and cyclooxygenase-2 (COX-2) was reported in ST-associated HNSCC by us [Sawhney,M. et al. (2007) Expression of NF-kappaB parallels COX-2 expression in oral precancer and cancer: association with smokeless tobacco. Int. J. Cancer, 120, 2545-2556]. In search of novel agents for treatment of HNSCC, we investigated the potential of guggulsterone (GS), (4,17(20)-pregnadiene-3,16-dione), a biosafe nutraceutical, in inhibiting ST- and nicotine-induced activation of NF-kB and signal transducer and activator of transcription (STAT) 3 pathways in HNSCC cells. GS inhibited the activation of NF-κB and STAT3 proteins in head and neck cancer cells. This inhibition of NF-kB by GS resulted from decreased phosphorylation and degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha the inhibitory subunit of NF-kB. Importantly, treatment of HNSCC cells with GS abrogated both ST- and nicotine-induced nuclear activation of NF-kB and pSTAT3 proteins and their downstream targets COX-2 and vascular endothelial growth factor. Furthermore, GS treatment decreased the levels of ST- and nicotine-induced secreted interleukin-6 in culture media of HNSCC cells. In conclusion, our findings demonstrated that GS treatment abrogates the effects of ST and nicotine on activation of NF-kB and STAT3 pathways in HNSCC cells that contribute to inflammatory and angiogenic responses as well as its progression and metastasis. These findings provide a biologic rationale for further clinical investigation of GS as an effective complementary agent for inhibiting ST-induced head and neck cancer. © The Author 2010. Published by Oxford University Press. All rights reserved.

Tripathi S.C.,All India Institute of Medical Sciences | Matta A.,York University | Kaur J.,All India Institute of Medical Sciences | Grigull J.,York University | And 9 more authors.
PLoS ONE | Year: 2010

Background: Tissue proteomic analysis of head and neck squamous cell carcinoma (HNSCC) and normal oral mucosa using iTRAQ (isobaric tag for relative and absolute quantitation) labeling and liquid chromatography-mass spectrometry, led to the identification of a panel of biomarkers including S100A7. In the multi-step process of head and neck tumorigenesis, the presence of dysplastic areas in the epithelium is proposed to be associated with a likely progression to cancer; however there are no established biomarkers to predict their potential of malignant transformation. This study aimed to determine the clinical significance of S100A7 overexpression in HNSCC. Methodology: Immunohistochemical analysis of S100A7 expression in HNSCC (100 cases), oral lesions (166 cases) and 100 histologically normal tissues was carried out and correlated with clinicopathological parameters and disease prognosis over 7 years for HNSCC patients. Overexpression of S100A7 protein was significant in oral lesions (squamous cell hyperplasia/dysplasia) and sustained in HNSCC in comparison with oral normal mucosa (ptrendlt;0.001). Significant increase in nuclear S100A7 was observed in HNSCC as compared to dysplastic lesions (p = 0.005) and associated with well differentiated squamous cell carcinoma (p = 0.031). Notably, nuclear accumulation of S100A7 also emerged as an independent predictor of reduced disease free survival (p = 0.006, Hazard ratio (HR = 7.6), 95% CI = 1.3-5.1) in multivariate analysis underscoring its relevance as a poor prognosticator of HNSCC patients. Conclusions: Our study demonstrated nuclear accumulation of S100A7 may serve as predictor of poor prognosis in HNSCC patients. Further, increased nuclear accumulation of S100A7 in HNSCC as compared to dysplastic lesions warrants a large-scale longitudinal study of patients with dysplasia to evaluate its potential as a determinant of increased risk of transformation of oral premalignant lesions.

Macha M.A.,All India Institute of Medical Sciences | Matta A.,York University | Chauhan S.S.,All India Institute of Medical Sciences | Siu K.W.M.,York University | And 4 more authors.
PLoS ONE | Year: 2011

Background: Epidemiological association of head and neck cancer with smokeless tobacco (ST) emphasizes the need to unravel the molecular mechanisms implicated in cancer development, and identify pharmacologically safe agents for early intervention and prevention of disease recurrence. Guggulsterone (GS), a biosafe nutraceutical, inhibits the PI3K/Akt pathway that plays a critical role in HNSCC development. However, the potential of GS to suppress ST and nicotine (major component of ST) induced HNSCC remains unexplored. We hypothesized GS can abrogate the effects of ST and nicotine on apoptosis in HNSCC cells, in part by activation of PI3K/Akt pathway and its downstream targets, Bax and Bad. Methods and Results: Our results showed ST and nicotine treatment resulted in activation of PI3K, PDK1, Akt, and its downstream proteins - Raf, GSK3β and pS6 while GS induced a time dependent decrease in activation of PI3K/Akt pathway. ST and nicotine treatment also resulted in induction of Bad and Bax phosphorylation, increased the association of Bad with 14-3-3ζresulting in its sequestration in the cytoplasm of head and neck cancer cells, thus blocking its pro-apoptotic function. Notably, GS pre-treatment inhibited ST/nicotine induced activation of PI3K/Akt pathway, and inhibited the Akt mediated phosphorylation of Bax and Bad. Conclusions: In conclusion, GS treatment not only inhibited proliferation, but also induced apoptosis by abrogating the effects of ST/nicotine on PI3K/Akt pathway in head and neck cancer cells. These findings provide a rationale for designing future studies to evaluate the chemopreventive potential of GS in ST/nicotine associated head and neck cancer. © 2011 Macha et al.

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