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Signalling Pathways in Metabolic Diseases and Cancers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (20 June 2025) | Viewed by 1323

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Department of Experimental and Clinical Medicine, University “Magna Graecia” Catanzaro, 88100 Catanzaro, Italy
Interests: molecular biology; cancer; cell line; cell culture; flow cytometry analysis; Western blotting; gene expression; sequencing; proteomics; seminoma cell line; prostate cancer cell lines
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Special Issue Information

Dear Colleagues,

Cellular signaling pathways play a crucial role in cellular communication and adaptation to the everchanging surrounding environment, ultimately governing key fate decisions such as cell death, survival, division, or senescence. Cellular signaling processes are elicited by a variety of extracellular and intracellular inducers, such as growth factors, nutrients, or stress and damage stimuli. Likewise, the transmission of information on activated signaling pathways can rely on a plethora of signaling mediators. Moreover, many of these pathways are connected to form signaling networks to ensure the right timing and termination of cell responses. Notably, the dysregulation of signaling pathways has been implicated in the pathogenesis of several diseases, including cancer, inflammation, and metabolic disorders.

We therefore welcome original papers that report novel research findings and results on different aspects of cellular signaling, with special attention paid to novel regulators of pro-survival/pro-apoptotic signaling cascades; advances in targeted therapeutic strategies to manipulate signaling cascades, such as immunological therapies and so on; and the investigation of dysregulated molecular mechanisms underlying several metabolic and immunological diseases and tumors.

This Special Issue is supervised by Dr. Bossio and assisted by Dr. Gallo and Dr. Palummo.

Dr. Sabrina Bossio
Guest Editor

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Keywords

  • cancer
  • prostate cancer
  • molecular signalling pathway
  • metabolic diseases
  • diabets
  • immunotherapy
  • immunological diseases

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Published Papers (2 papers)

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Research

17 pages, 5071 KiB  
Article
Defactinib in Combination with Mitotane Can Be an Effective Treatment in Human Adrenocortical Carcinoma
by Henriett Butz, Lőrinc Pongor, Lilla Krokker, Borbála Szabó, Katalin Dezső, Titanilla Dankó, Anna Sebestyén, Dániel Sztankovics, József Tóvári, Sára Eszter Surguta, István Likó, Katalin Mészáros, Andrea Deák, Fanni Fekete, Ramóna Vida, László Báthory-Fülöp, Erika Tóth, Péter Igaz and Attila Patócs
Int. J. Mol. Sci. 2025, 26(13), 6539; https://doi.org/10.3390/ijms26136539 - 7 Jul 2025
Viewed by 486
Abstract
Adrenocortical carcinoma (ACC) is an aggressive cancer with a poor prognosis. Mitotane, the only FDA-approved treatment for ACC, targets adrenocortical cells and reduces cortisol levels. Although it remains the cornerstone of systemic therapy, its overall impact on long-term outcomes is still a matter [...] Read more.
Adrenocortical carcinoma (ACC) is an aggressive cancer with a poor prognosis. Mitotane, the only FDA-approved treatment for ACC, targets adrenocortical cells and reduces cortisol levels. Although it remains the cornerstone of systemic therapy, its overall impact on long-term outcomes is still a matter of ongoing clinical debate. Drug repurposing is a cost-effective way to identify new therapies, and defactinib, currently in clinical trials as part of combination therapies for various solid tumours, may enhance ACC treatment. We aimed to assess its efficacy in combination with mitotane. We tested the combination of mitotane and defactinib in H295R, SW13, and mitotane-sensitive and -resistant HAC15 cells, using functional assays, transcriptomic profiling, 2D and 3D cultures, bioprinted tissues, and xenografts. We assessed drug interactions with NMR and toxicity in vivo, as mitotane and defactinib have never been previously administered together. Genomic data from 228 human ACC and 158 normal adrenal samples were also analysed. Transcriptomic analysis revealed dysregulation of focal adhesion along with mitotane-related pathways. Focal adhesion kinase (FAK) signalling was enhanced in ACC compared to normal adrenal glands, with PTK2 (encoding FAK) upregulated in 44% of tumour samples due to copy number alterations. High FAK signature scores correlated with worse survival outcomes. FAK inhibition by defactinib, both alone and in combination with mitotane, showed effective anti-tumour activity in vitro. No toxicity or drug—drug interactions were observed in vivo. Combination treatment significantly reduced tumour volume and the number of macrometastases compared to those in the mitotane and control groups, with defactinib-treated tumours showing increased necrosis in xenografts. Defactinib combined with conventionally used mitotane shows promise as a novel combination therapy for ACC and warrants further investigation. Full article
(This article belongs to the Special Issue Signalling Pathways in Metabolic Diseases and Cancers)
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15 pages, 3257 KiB  
Article
Inhibiting the TGF-β1 Pathway Reduces the Aggressiveness of Intrahepatic CCA HuCCT1 CD90-Positive Cells
by Elena Pizzuto, Serena Mancarella, Isabella Gigante, Grazia Serino, Francesco Dituri, Emanuele Piccinno, Isabel Fabregat and Gianluigi Giannelli
Int. J. Mol. Sci. 2025, 26(11), 4973; https://doi.org/10.3390/ijms26114973 - 22 May 2025
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Abstract
Molecular mechanisms responsible for the poor prognosis in patients with intrahepatic cholangiocarcinoma (CCA) are still unknown, but stem cell marker Cluster Differentiation 90 (CD90) has been reported to be associated with a more aggressive cancer phenotype. In this scenario, the TGF-β1 signaling pathway [...] Read more.
Molecular mechanisms responsible for the poor prognosis in patients with intrahepatic cholangiocarcinoma (CCA) are still unknown, but stem cell marker Cluster Differentiation 90 (CD90) has been reported to be associated with a more aggressive cancer phenotype. In this scenario, the TGF-β1 signaling pathway likely has a role as master gene regulator. Aim of the study is to investigate the role of CD90 in iCCA aggressiveness. The molecular profile of HuCCT1/CD90+ and HuCCT1/CD90− cells was obtained through transcriptomic analysis (NGS). Bioinformatic data were confirmed in both cell lines by qRT-PCR and Western blot. Cells were treated with Gemcitabine in monotherapy or in combination with Galunisertib, a selective inhibitor of TGF-βRI, in 2D and 3D models. HuCCT1/CD90+ cells are more proliferative, less migratory, and resistant to Gemcitabine treatment. HuCCT1/CD90+ cells also express lower levels of TGF-β1 compared to /CD90− cell lines. Finally, HuCCT1/CD90+ cells are resistant to Gemcitabine, while the combination of Gemcitabine and Galunisertib displays a synergistic effect on HuCCT1/CD90+ cell proliferation. These results underline that CD90-induced Gemcitabine resistance can be overcome by adding a TGFβ1 inhibitor such as Galunisertib, thereby moving further toward a precision medicine approach in patients with iCCA. Full article
(This article belongs to the Special Issue Signalling Pathways in Metabolic Diseases and Cancers)
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