Proteomics study of medullary thyroid carcinomas expressing RET germ‐line mutations: Identification of new signaling elements

Gorla, L.; Mondellini, Piera; Cuccuru, Giuditta; Miccichè, Francesca; Cassinelli, Giuliana; Cremona, Mattia; Lanzi, Cinzia; Bongarzone, Italia

doi:10.1002/mc.20474

Cited by 25 publications

(22 citation statements)

References 37 publications

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“…For protein profiling of DOHH-2 apoptotic and necrotic cell bodies, protein bands were excised from Coomassie-stained preparative gels and processed as previously described (26). Matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry was carried out with a Voyager-DE STR (Applied Biosystems), equipped with a nitrogen laser (337 nm).…”

Section: Western Blotmentioning

confidence: 99%

Improved Clinical Outcome in Indolent B-Cell Lymphoma Patients Vaccinated with Autologous Tumor Cells Experiencing Immunogenic Death

et al. 2010

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Increasing evidence argues that the success of an anticancer treatment may rely on immunoadjuvant side effects including the induction of immunogenic tumor cell death. Based on the assumption that this death mechanism is a similar prerequisite for the efficacy of an active immunotherapy using killed tumor cells, we examined a vaccination strategy using dendritic cells (DC) loaded with apoptotic and necrotic cell bodies derived from autologous tumors. Using this approach, clinical and immunologic responses were achieved in 6 of 18 patients with relapsed indolent non-Hodgkin's lymphoma (NHL). The present report illustrates an impaired ability of the neoplastic cells used to vaccinate nonresponders to undergo immunogenic death on exposure to a cell death protocol based on heat shock, γ-ray, and UVC ray. Interestingly, when compared with doxorubicin, this treatment increased surface translocation of calreticulin and cellular release of high-mobility group box 1 and ATP in histologically distinct NHL cell lines. In contrast, treated lymphoma cells from responders displayed higher amounts of calreticulin and heat shock protein 90 (HSP90) compared with those from nonresponders and boosted the production of specific antibodies when loaded into DCs for vaccination. Accordingly, the extent of calreticulin and HSP90 surface expression in the DC antigenic cargo was significantly associated with the clinical and immunologic responses achieved. Our results indicate that a positive clinical effect is obtained when immunogenically killed autologous neoplastic cells are used for the generation of a DC-based vaccine. Therapeutic improvements may thus be accomplished by circumventing the tumor-impaired ability to undergo immunogenic death and prime the antitumor immune response. Cancer Res; 70(22); 9062-72. ©2010 AACR.

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Section: Western Blotmentioning

confidence: 99%

Improved Clinical Outcome in Indolent B-Cell Lymphoma Patients Vaccinated with Autologous Tumor Cells Experiencing Immunogenic Death

et al. 2010

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“…We found that activation of Akt and Erks was inhibited by RPI-1 in TT cells, with the consequent activation of Bad and caspase-9, resulting in apoptosis induction through the intrinsic pathway [15]. Recently, Fas-associated phosphatase-1 (Fap-1, PTPN13) has been identified as one of the RPI-1-sensitive components in the signaling network of RET mutant-expressing MTC cells [21]. Fap-1, a large nonreceptor protein tyrosine-phosphatase (PTP), is the only protein known to associate with the C-terminal negative regulatory domain of CD95 (Fas/APO1) death receptor (DR) [22,23].…”

Section: Page 4 Of 38mentioning

confidence: 95%

Interplay between Ret and Fap-1 regulates CD95-mediated apoptosis in medullary thyroid cancer cells

Nicolini

Cassinelli

Cuccuru

et al. 2011

Biochemical Pharmacology

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Emerging evidence suggests that Ret oncoproteins expressed in medullary thyroid cancer (MTC) might evade the pro-apoptotic function of the dependence receptor proto-Ret by directly impacting the apoptosis machinery. Identification of the molecular determinants of the interplay between Ret signaling and apoptosis might provide a relevant contribution to the optimization of Ret-targeted therapies. Here, we describe the cross-talk between Ret-M918T oncogenic mutant responsible for type 2B multiple endocrine syndrome (MEN2B), and components of death receptor-mediated extrinsic apoptosis pathway. In the human MEN2B-type MTC cell line MZ-CRC-1 expressing Ret-M918T, Ret was found associated with Fap-1, known as inhibitor of the CD95 death receptor trafficking to the cell membrane, and with procaspase-8, the initiator pro-form caspase in the extrinsic apoptosis pathway. Cell treatment with the anti-tumor Ret kinase inhibitor RPI-1 inhibited tyrosine phosphorylation of procaspase-8, likely inducing its local activation, followed by downregulation of both Ret and

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“…Protein concentrations were determined with the bicinchoninic acid (BCA) assay (Bio-Rad Laboratories). Protein separation by electrophoresis (SDS-PAGE) and electroblotting were performed as previously described (Gorla et al 2009) western blot quantifications were performed using Quantity one software (Bio-Rad).…”

Section: Facs Analysismentioning

confidence: 99%

4-IPP, a selective MIF inhibitor, causes mitotic catastrophe in thyroid carcinomas

Varinelli¹,

Caccia²,

Volpi³

et al. 2015

Endocrine-Related Cancer

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Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is over-expressed in several human neoplastic cells. When MIF binds its receptor (CD74) and co-receptor (CD44), it initiates signaling cascades that orchestrate cell proliferation and survival, and it can directly modulate the activity of AMPK. These activities indicate that MIF potentially regulates cell survival and metabolism. We found that MIF was primarily co-expressed with CD74 in 16 out of 23 papillary thyroid carcinoma (PTC) and in all the 27 available anaplastic thyroid carcinoma (ATC) biopsy samples. MIF and CD74 were co-expressed in TPC-1 and HTC-C3 cell lines. The selective MIF inhibitor, 4-iodo-6-phenylpyrimidine (4-IPP), blocked MIF/CD74 internalization, activated JNK, and dosedependently inhibited proliferation inducing apoptosis and mitotic cell death. In two CD74-negative cell lines, NIM-1 and K1, 4-IPP treatment partially reduced proliferation. Coordinated MIF and CD74 expression appeared to confer in tumor cells the plasticity necessary to escape cell cycle regulation, metabolic changes, and stress conditions. MIF/CD74 signaling removal made cells susceptible to apoptosis and mitotic cell death. This finding suggests a possible avenue for targeting DNA endoreduplication, thus preventing the proliferation of therapy-resistant cell subpopulations. This study highlights MIF/CD74 axis as an important player in the biology of aggressive thyroid neoplasms.

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Proteomics study of medullary thyroid carcinomas expressing RET germ‐line mutations: Identification of new signaling elements

Cited by 25 publications

References 37 publications

Improved Clinical Outcome in Indolent B-Cell Lymphoma Patients Vaccinated with Autologous Tumor Cells Experiencing Immunogenic Death

Improved Clinical Outcome in Indolent B-Cell Lymphoma Patients Vaccinated with Autologous Tumor Cells Experiencing Immunogenic Death

Interplay between Ret and Fap-1 regulates CD95-mediated apoptosis in medullary thyroid cancer cells

4-IPP, a selective MIF inhibitor, causes mitotic catastrophe in thyroid carcinomas

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