Functional Protein Pathway Activation Mapping of the Progression of Normal Skin to Squamous Cell Carcinoma

Einspahr, Janine G.; Calvert, Valerie; Alberts, David S.; Curiel‐Lewandrowski, Clara; Warneke, James; Krouse, Robert S.; Stratton, Steven P.; Liotta, Lance A.; Longo, Caterina; Pellicani, Giovanni; Sagerman, Paul; Bermudez, Yira; Deng, Jianghong; Bowden, G. Timothy; Petricoin, Emanuel F.

doi:10.1158/1940-6207.capr-11-0427

Cited by 84 publications

(92 citation statements)

References 40 publications

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“…Furthermore, UVB-induces phosphorylation of 4EBP1, S6K, and AKT, suggesting an important role of the mTOR pathway in tumor initiation and progression (47). In our studies, pretreatment with C3 complex and FGFR inhibitor attenuated UVB-induced mTORC1 and mTORC2 activation.…”

Section: Discussionsupporting

confidence: 56%

Photopreventive Effect and Mechanism of AZD4547 and Curcumin C3 Complex on UVB-Induced Epidermal Hyperplasia

Khandelwal

Rong

Moore-Medlin

et al. 2016

Cancer Prevention Research

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Aggressive cutaneous squamous cell carcinoma (cSCC) of the skin is the second most common type of skin cancer in the United States due to high exposure to ultraviolet B (UVB) radiation. In our previous studies, Curcumin C3 complex (C3), a standardized preparation of three curcumonoids, delayed UVB-induced tumor incidence and inhibited multiplicity. Exposure to UVB activates mTOR and FGFR signaling that play a key role in skin tumorigenesis. The purpose of this study was to investigate the efficacy of C3 complex to afford protection against acute UVB-induced hyperproliferation by targeting the mTOR and FGFR signaling pathways. Pretreatment with C3 complex significantly inhibited UVB-induced FGF-2 induction, FGF-2-induced cell proliferation, progression and colony formation, mTORC1 and mTORC2 activation, and FGFR2 phosphorylation in the promotion-sensitive JB6 cells epithelial cells.Further, FGFR was critical for UVB-induced mTOR activation, suggesting an important role of FGFR2 in UVB-induced mTOR signaling. SKH-1 mice pretreated with C3 (15 mg/kg/b.w.) for 2 weeks followed by a single exposure to UVB (180 mj/cm 2 ) significantly attenuated UVB-induced mTORC1, mTORC2, and FGFR2 activation. To further assess the role of FGFR in UVBinduced hyperproliferation, SKH-1 mice were pretreated with AZD4547 (5 mg/kg/b.w.); a selective pan-FGFR kinase inhibitor followed by single exposure to UVB (180 mj/cm 2 ). AZD4547 significantly inhibited UVB-induced mTORC1 and mTORC2 activation, epidermal hyperplasia and hyperproliferation. Our studies underscore the importance of FGFR signaling in UVBinduced acute skin changes and the role of FGFR/mTOR signaling in mediating the effects of C3 complex in the pathogenesis of skin cancer. Cancer Prev Res; 9(4); 296-304. Ó2016 AACR.

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Section: Discussionsupporting

confidence: 56%

Photopreventive Effect and Mechanism of AZD4547 and Curcumin C3 Complex on UVB-Induced Epidermal Hyperplasia

Khandelwal

Rong

Moore-Medlin

et al. 2016

Cancer Prevention Research

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“…Squamous cell carcinomas typically have hyperactive EGFR/ERK and PI3K/AKT/mTOR signaling pathways. [26][27][28]31 One consequence of activation of these pathways is phosphorylation of the ribosomal protein S6. S6 is a component of the 40S ribosomal subunit and is thought to have a role in modulating efficiency of mRNA translation initiation.…”

Section: Discussionmentioning

confidence: 99%

“…24,25 Squamous cell carcinomas of the interfollicular epidermis, oral cavity, oropharynx, and lung very frequently have gene mutations and amplifications that hyperactivate their EGFR/ERK signaling pathway. [26][27][28] Our recent study identified EGFR/ERK signal pathway hyperactivation as necessary and sufficient to drive laminin g 2 overexpression in cultured human premalignant epithelial and squamous cell carcinoma cell lines and also found that the HPV16 E6 oncoprotein also induces laminin g 2 overexpression. 29 Laminin g 2 overexpression proved to require the ERK-activated RSK kinase and to correlate with increased phosphorylation of the translation factor eIF4B at S442 and of ribosomal protein S6 at S235/236.…”

mentioning

confidence: 96%

Phosphorylated S6 as an immunohistochemical biomarker of vulvar intraepithelial neoplasia

et al. 2013

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As life expectancy lengthens, cases of non-viral-associated vulvar squamous cell carcinoma and its precursor lesion, so-called differentiated vulvar intraepithelial neoplasia (VIN), continue to increase in frequency. Differentiated VIN often is difficult to recognize and failure to detect it before invasion results in morbidity and mortality. Thus, identification of a reliable biomarker for this type of lesion would be of great clinical benefit. Our recent studies have identified activation (ser235/236 phosphorylation) of ribosomal protein S6 (p-S6) in basal epithelial cells as an event that precedes and accompanies laminin c 2 overexpression in most preinvasive oral dysplasias. To test this as a potential biomarker of vulvar dysplasia, we immunostained seven differentiated VINs and nine papillomavirusrelated 'classic' VINs, most of which were associated with carcinoma, for p-S6. All carcinomas, all differentiated VINs, and most classic VINs contained regions of p-S6 staining in the basal layer, whereas basal and parabasal cells of normal vulvar epithelium and hyperplastic and inflamed lesions lacking cellular atypia were p-S6 negative. Laminin c 2 was expressed in a subset of VINs, always occurring within basal p-S6 positive regions, as we had found previously for oral dysplasias. Lichen sclerosus is considered a potential precursor of vulvar carcinoma. Two lichen sclerosus lesions of patients with a concurrent carcinoma and one of six lichen sclerosus lesions without atypia or known concurrent carcinoma were basal p-S6 positive. In summary, there is a distinct difference in p-S6 basal cell layer staining between benign and neoplastic vulvar squamous epithelium, with consistent staining of differentiated VIN and of some lichen sclerosus lesions. These results support further studies to assess the potential of p-S6 as a biomarker to identify vulvar lesions at risk of progressing to invasive cancer.

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“…Spearman's Rho correlations were also taken into consideration for each experimental set, with experimental sets ultimately being compared with each other to isolate endpoints unique to adipogenesis. Alterations in signaling for inhibitor treated experimental sets were further examined using CScape pathway maps to reflect signaling pathway changes relative to the related untreated samples (25). These maps examined alterations in the early and late signaling events by analysis of day 4 and day 8 data.…”

Section: Methodsmentioning

confidence: 99%

Dynamic Protein Pathway Activation Mapping of Adipose-Derived Stem Cell Differentiation Implicates Novel Regulators of Adipocyte Differentiation

Wilson

Liotta

PetricoinIII

2013

Molecular & Cellular Proteomics

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Next to embryonic stem cell research, adult stem cell research is providing a promising alternative for enhanced tissue regeneration and transplantation. The key biochemical networks controlling the differentiation processes regulating stem cell biology remain largely disputed and or undefined, contributing to a lack of knowledge of the principle phosphoregulatory events propagating signal transduction. To effectively monitor these events relative to adipocyte differentiation, this study utilized a high throughput reverse phase protein microarray platform and characterized adult adipose-derived stem cell (ASC) differentiation through the monitoring of ϳ100 phosphospecific endpoints with 33 distinct time points examined across 14 days. This kinetic-based analysis showed time ordered signal transduction ultimately implicating pathways correlated with adipogenic differentiation. To further validate the causal significance of these network activations, pharmacological targeting was implemented to include the chemical inhibitors MAPK inhibitor PD169316, rapamycin, and HNMPA-(AM) 3 yielding partial or complete disruption of adipocytic differentiation, as noted by a decrease or lack of lipid formation within the mature adipocytes. Based on this analysis, v-crk sarcoma virus CT10 oncogene homolog (CRKII) and c-abl oncogene 1, non-receptor tyrosine kinase (c-ABL) were implicated as novel key regulators of adipocyte differentiation, with v-akt murine thymoma viral oncogene (AKT), mammalian target of rapamycin (mTOR), and SMAD family member (SMAD) pathways being implicated as secondary regulators. This dynamic molecular profiling provides a novel insight into the signaling architecture of mesenchymal stem cell differentiation and may be useful in the development of therapeutic modulators for clinical applications; in addition to advancing the collective understanding of key cellular processes, ultimately contributing to more confident stem cell manipulation. Molecular & Cellular

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Functional Protein Pathway Activation Mapping of the Progression of Normal Skin to Squamous Cell Carcinoma

Cited by 84 publications

References 40 publications

Photopreventive Effect and Mechanism of AZD4547 and Curcumin C3 Complex on UVB-Induced Epidermal Hyperplasia

Photopreventive Effect and Mechanism of AZD4547 and Curcumin C3 Complex on UVB-Induced Epidermal Hyperplasia

Phosphorylated S6 as an immunohistochemical biomarker of vulvar intraepithelial neoplasia

Dynamic Protein Pathway Activation Mapping of Adipose-Derived Stem Cell Differentiation Implicates Novel Regulators of Adipocyte Differentiation

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