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Molecular and Cellular Mechanisms of Cancers: Pancreatic Cancer

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A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 51430

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Special Issue Editor

Dr. Carmen Guerra

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Guest Editor

Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain
Interests: pancreatic cancer; lung cancer; mouse models; ras signaling; precision medicine; therapeutic strategies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pancreatic ductal adenocarcinoma is one of the most lethal cancers with an increasing incidence rate, poor prognosis, and an extremely low 5-year survival rate. This is not only due to the aggressiveness of the tumor, but also due to the late diagnosis and the lack of effective treatments. The majority of the patients are in an advanced stage at the time of diagnosis and therefore, surgery is not an option. Furthermore, the efficacy of radiotherapy and chemotherapy is very poor, and immunotherapy and personalized medicine are not applied yet to pancreatic cancer patients. However, big efforts are currently underway to change this adverse situation. This Special Issue seeks reviews and original papers covering the more recent studies related to the biology (cell of origin, exosomes, stroma, etc.), molecular biology (classification of tumors, driver mutations with therapeutic value, etc.), models for preclinical studies (mini-pig, organoids, organotypic models, PDX models, new mouse models, etc.) and development of new strategies for prevention (uncover risk factors, etc.), early diagnosis (molecular imaging, markers in liquid biopsy, etc.), and therapy (targeted therapy, immunotherapy, etc.).

Dr. Carmen Guerra
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

stroma
molecular subtypes of pancreatic cancer
cell of origin
exosomes
organoids
organotypic models
genetically engineered mouse models
PDX models
mini-pig
targeted therapy
immunotherapy
risk factors
markers for early diagnosis and prognosis

Published Papers (11 papers)

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Research

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17 pages, 5159 KiB

Open AccessArticle

Targeted PARP Inhibition Combined with FGFR1 Blockade is Synthetically Lethal to Malignant Cells in Patients with Pancreatic Cancer

by Shiue-Wei Lai, Oluwaseun Adebayo Bamodu, Jia-Hong Chen, Alexander TH Wu, Wei-Hwa Lee, Tsu-Yi Chao and Chi-Tai Yeh

Cells 2020, 9(4), 911; https://doi.org/10.3390/cells9040911 - 08 Apr 2020

Cited by 9 | Viewed by 3423

Abstract

The role and therapeutic promise of poly-ADP ribose polymerase (PARP) inhibitors in anticancer chemotherapy are increasingly being explored, particularly in adjuvant or maintenance therapy, considering their low efficacy as monotherapy agents and their potentiating effects on concurrently administered contemporary chemotherapeutics. Against the background of increasing acquired resistance to FGFR1 inhibitors and our previous work, which partially demonstrated the caspase-3/PARP-mediated antitumor and antimetastatic efficacy of PD173074, a selective FGFR1 inhibitor, against ALDH-high/FGFR1-rich pancreatic ductal adenocarcinoma (PDAC) cells, we investigated the probable synthetic lethality and therapeutic efficacy of targeted PARP inhibition combined with FGFR1 blockade in patients with PDAC. Using bioinformatics-based analyses of gene expression profiles, co-occurrence and mutual exclusivity, molecular docking, immunofluorescence staining, clonogenicity, Western blotting, cell viability or cytotoxicity screening, and tumorsphere formation assays, we demonstrated that FGFR1 and PARP co-occur, form a complex, and reduce survival in patients with PDAC. Furthermore, FGFR1 and PARP expression was upregulated in FGFR1 inhibitor (dasatinib)-resistant PDAC cell lines SU8686, MiaPaCa2, and PANC-1 compared with that in sensitive cell lines Panc0403, Panc0504, Panc1005, and SUIT-2. Compared with the limited effect of single-agent olaparib (PARP inhibitor) or PD173074 on PANC-1 and SUIT-2 cells, low-dose combination (olaparib + PD173074) treatment significantly, dose-dependently, and synergistically reduced cell viability, upregulated cleaved PARP, pro-caspase (CASP)-9, cleaved-CASP9, and cleaved-CASP3 protein expression, and downregulated Bcl-xL protein expression. Furthermore, combination treatment markedly suppressed the clonogenicity and tumorsphere formation efficiency of PDAC cells regardless of FGFR1 inhibitor-resistance status and enhanced RAD51 and γ-H2AX immunoreactivity. In vivo studies have shown that both early and late initiation of combination therapy markedly suppressed tumor xenograft growth and increase in weight, although the effect was more pronounced in the early initiation group. In conclusion, FGFR1 inhibitor-resistant PDAC cells exhibited sensitivity to PD173074 after olaparib-mediated loss of PARP signaling. The present FGFR1/PARP-mediated synthetic lethality proof-of-concept study provided preclinical evidence of the feasibility and therapeutic efficacy of combinatorial FGFR1/PARP1 inhibition in human PDAC cell lines. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Pancreatic Cancer)

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17 pages, 7043 KiB

Open AccessArticle

Novel Mechanistic Insight into the Anticancer Activity of Cucurbitacin D against Pancreatic Cancer (Cuc D Attenuates Pancreatic Cancer)

by Mohammed Sikander, Shabnam Malik, Sheema Khan, Sonam Kumari, Neeraj Chauhan, Parvez Khan, Fathi T. Halaweish, Bhavin Chauhan, Murali M. Yallapu, Meena Jaggi and Subhash C. Chauhan

Cells 2020, 9(1), 103; https://doi.org/10.3390/cells9010103 - 31 Dec 2019

Cited by 21 | Viewed by 4863

Abstract

Pancreatic cancer (PanCa) is one of the leading causes of death from cancer in the United States. The current standard treatment for pancreatic cancer is gemcitabine, but its success is poor due to the emergence of drug resistance. Natural products have been widely investigated as potential candidates in cancer therapies, and cucurbitacin D (Cuc D) has shown excellent anticancer properties in various models. However, there is no report on the therapeutic effect of Cuc D in PanCa. In the present study, we investigated the effects of the Cuc D on PanCa cells in vitro and in vivo. Cuc D inhibited the viability of PanCa cells in a dose and time dependent manner, as evident by MTS assays. Furthermore, Cuc D treatment suppressed the colony formation, arrest cell cycle, and decreased the invasion and migration of PanCa cells. Notably, our findings suggest that mucin 13 (MUC13) is down-regulated upon Cuc D treatment, as demonstrated by Western blot and qPCR analyses. Furthermore, we report that the treatment with Cuc D restores miR-145 expression in PanCa cells/tissues. Cuc D treatment suppresses the proliferation of gemcitabine resistant PanCa cells and inhibits RRM1/2 expression. Treatment with Cuc D effectively inhibited the growth of xenograft tumors. Taken together, Cuc D could be utilized as a novel therapeutic agents for the treatment/sensitization of PanCa. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Pancreatic Cancer)

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13 pages, 1952 KiB

Open AccessFeature PaperArticle

Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer

by Marie C. Hasselluhn, Lukas Klein, Melanie S. Patzak, Sören M. Buchholz, Philipp Ströbel, Volker Ellenrieder, Patrick Maisonneuve and Albrecht Neesse

Cells 2020, 9(1), 58; https://doi.org/10.3390/cells9010058 - 24 Dec 2019

Cited by 9 | Viewed by 3645

Abstract

The Kras^G12D/+;LSL-Trp53^R172H/+;Pdx-1-Cre (KPC) mouse model is frequently employed for preclinical therapeutic testing, in particular in regard to antistromal therapies. Here, we investigate the prognostic implications of histopathological features that may guide preclinical trial design. Pancreatic tumor tissue from n = 46 KPC mice was quantitatively analyzed using immunohistochemistry and co-immunofluorescence for proliferation (Ki67), mitotic rate (phospho-Histone 3, PHH3), apoptosis (cleaved caspase-3, CC3), collagen content, secreted protein acidic and rich in cysteine (SPARC), hyaluronic acid (HA), and α-smooth muscle actin (α-SMA). Furthermore, mean vessel density (MVD), mean lumen area (MLA), grading, activated stroma index (ASI), and fibroblast-proliferation rate (α-SMA/Ki67) were assessed. Univariate analysis using the Kaplan–Meier estimator and Cox regression model for continuous variables did not show association between survival and any of the analyzed parameters. Spearman correlation demonstrated that desmoplasia was inversely correlated with differentiated tumor grade (ρ = −0.84). Ki67 and PHH3 synergized as proliferation markers (ρ = 0.54), while SPARC expression was positively correlated with HA content (ρ = 0.37). MVD and MLA were correlated with each other (ρ = 0.31), while MLA positively correlated with CC3 (ρ = 0.45). Additionally, increased MVD was correlated with increased fibroblast proliferation rate (α-SMA + Ki67; ρ = 0.36). Our pilot study provides evidence that individual histopathological parameters of the primary tumor of KPC mice are not associated with survival, and may hint at the importance of systemic tumor-related effects such as cachexia. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Pancreatic Cancer)

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18 pages, 4489 KiB

Open AccessArticle

Interleukin 21 Receptor/Ligand Interaction Is Linked to Disease Progression in Pancreatic Cancer

by Alica Linnebacher, Philipp Mayer, Nicole Marnet, Frank Bergmann, Esther Herpel, Steffie Revia, Libo Yin, Li Liu, Thilo Hackert, Thomas Giese, Ingrid Herr and Matthias M. Gaida

Cells 2019, 8(9), 1104; https://doi.org/10.3390/cells8091104 - 18 Sep 2019

Cited by 11 | Viewed by 4289

Abstract

Pancreatic ductal adenocarcinoma (PDAC) displays a marked fibro-inflammatory microenvironment in which infiltrated immune cells fail to eliminate the tumor cells and often—rather paradoxically—promote tumor progression. Of special interest are tumor-promoting T cells that assume a Th17-like phenotype because their presence in PDAC tissue is associated with a poor prognosis. In that context, the role of IL-21, a major cytokine released by Th17-like cells, was assessed. In all tissue samples (n = 264) IL-21⁺ immune cells were detected by immunohistochemistry and high density of those cells was associated with poor prognosis. In the majority of patients (221/264), tumor cells expressed the receptor for IL-21 (IL-21R) and also a downstream target of IL-21, Blimp-1 (199/264). Blimp-1 expression closely correlated with IL-21R expression and multivariate analysis revealed that expression of both IL-21R and Blimp-1 was associated with shorter survival time of the patients. In vitro data using pancreatic tumor cells lines provided a possible explanation: IL-21 activated ERK and STAT3 pathways and upregulated Blimp-1. Moreover, IL-21 increased invasion of tumor cell lines in a Blimp-1-dependent manner. As an in vivo correlate, an avian xenograft model was used. Here again Blimp-1 expression was significantly upregulated in IL-21 stimulated tumor cells. In summary, our data showed an association of IL-21⁺ immune cell infiltration and IL-21 receptor expression in PDAC with poor survival, most likely due to an IL-21-mediated promotion of tumor cell invasion and enhanced colony formation, supporting the notion of the tumor-promoting abilities of the tumor microenvironment. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Pancreatic Cancer)

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23 pages, 5355 KiB

Open AccessArticle

Overcoming Immunological Resistance Enhances the Efficacy of a Novel Anti-tMUC1-CAR T Cell Treatment against Pancreatic Ductal Adenocarcinoma

by Mahboubeh Yazdanifar, Ru Zhou, Priyanka Grover, Chandra Williams, Mukulika Bose, Laura J. Moore, Shu-ta Wu, John Maher, Didier Dreau and Pinku Mukherjee

Cells 2019, 8(9), 1070; https://doi.org/10.3390/cells8091070 - 11 Sep 2019

Cited by 43 | Viewed by 6566

Abstract

Chimeric antigen receptor (CAR) T cells have shown remarkable success in treating hematologic cancers. However, this efficacy has yet to translate to treatment in solid tumors. Pancreatic ductal adenocarcinoma (PDA) is a fatal malignancy with poor prognosis and limited treatment options. We have developed a second generation CAR T cell using the variable fragments of a novel monoclonal antibody, TAB004, which specifically binds the tumor-associated-MUC1 (tMUC1). tMUC1 is overexpressed on ~85% of all human PDA. We present data showing that TAB004-derived CAR T cells specifically bind to tMUC1 on PDA cells and show robust killing activity; however, they do not bind or kill normal epithelial cells. We further demonstrated that the tMUC1-CAR T cells control the growth of orthotopic pancreatic tumors in vivo. We witnessed that some PDA cells (HPAFII and CFPAC) were refractory to CAR T cell treatment. qPCR analysis of several genes revealed overexpression of indoleamine 2, 3-dioxygenases-1 (IDO1), cyclooxygenase 1 and 2 (COX1/2), and galectin-9 (Gal-9) in resistant PDA cells. We showed that combination of CAR T cells and biological inhibitors of IDO1, COX1/2, and Gal-9 resulted in significant enhancement of CAR T cell cytotoxicity against PDA cells. Overcoming PDA resistance is a significant advancement in the field. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Pancreatic Cancer)

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14 pages, 3687 KiB

Open AccessArticle

Preclinical Evaluation of 1,2-Diamino-4,5-Dibromobenzene in Genetically Engineered Mouse Models of Pancreatic Cancer

by Robert G. Goetze, Soeren M. Buchholz, Ning Ou, Qinrong Zhang, Shilpa Patil, Markus Schirmer, Shiv K. Singh, Volker Ellenrieder, Elisabeth Hessmann, Qing-Bin Lu and Albrecht Neesse

Cells 2019, 8(6), 563; https://doi.org/10.3390/cells8060563 - 09 Jun 2019

Cited by 5 | Viewed by 3818

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to standard chemo- and radiotherapy. Recently, a new class of non-platinum-based halogenated molecules (called FMD compounds) was discovered that selectively kills cancer cells. Here, we investigate the potential of 1,2-Diamino-4,5-dibromobenzene (2Br-DAB) in combination with standard chemotherapy and radiotherapy in murine and human PDAC. Methods: Cell viability and colony formation was performed in human (Panc1, BxPC3, PaTu8988t, MiaPaCa) and three murine LSL-Kras^G12D/+;LSL-Trp53^R172H/+;Pdx-1-Cre (KPC) pancreatic cancer cell lines. In vivo, preclinical experiments were conducted in LSL-Kras^G12D/+;p48-Cre (KC) and KPC mice using 2Br-DAB (7 mg/kg, i.p.), +/- radiation (10 × 1.8 Gy), gemcitabine (100 mg/kg, i.p.), or a combination. Tumor growth and therapeutic response were assessed by high-resolution ultrasound and immunohistochemistry. Results: 2Br-DAB significantly reduced cell viability in human and murine pancreatic cancer cell lines in a dose-dependent manner. In particular, colony formation in human Panc1 cells was significantly decreased upon 25 µM 2Br-DAB + radiation treatment compared with vehicle control (p = 0.03). In vivo, 2Br-DAB reduced tumor frequency in KC mice. In the KPC model, 2Br-DAB or gemcitabine monotherapy had comparable therapeutic effects. Furthermore, the combination of gemcitabine and 2Br-DAB or 2Br-DAB and 18 Gy irradiation showed additional antineoplastic effects. Conclusions: 2Br-DAB is effective in killing pancreatic cancer cells in vitro. 2Br-DAB was not toxic in vivo, and additional antineoplastic effects were observed in combination with irradiation. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Pancreatic Cancer)

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Review

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25 pages, 774 KiB

Open AccessReview

Pancreatic Fibroblast Heterogeneity: From Development to Cancer

by Paloma E. Garcia, Michael K. Scales, Benjamin L. Allen and Marina Pasca di Magliano

Cells 2020, 9(11), 2464; https://doi.org/10.3390/cells9112464 - 12 Nov 2020

Cited by 30 | Viewed by 4567

Abstract

Pancreatic ductal adenocarcinoma (PDA) is characterized by an extensive fibroinflammatory microenvironment that accumulates from the onset of disease progression. Cancer-associated fibroblasts (CAFs) are a prominent cellular component of the stroma, but their role during carcinogenesis remains controversial, with both tumor-supporting and tumor-restraining functions reported in different studies. One explanation for these contradictory findings is the heterogeneous nature of the fibroblast populations, and the different roles each subset might play in carcinogenesis. Here, we review the current literature on the origin and function of pancreatic fibroblasts, from the developing organ to the healthy adult pancreas, and throughout the initiation and progression of PDA. We also discuss clinical approaches to targeting fibroblasts in PDA. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Pancreatic Cancer)

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20 pages, 2036 KiB

Open AccessReview

The Role of Autophagy in Pancreatic Cancer: From Bench to the Dark Bedside

by Kıvanç Görgülü, Kalliope N. Diakopoulos, Ezgi Kaya-Aksoy, Katrin J. Ciecielski, Jiaoyu Ai, Marina Lesina and Hana Algül

Cells 2020, 9(4), 1063; https://doi.org/10.3390/cells9041063 - 24 Apr 2020

Cited by 28 | Viewed by 4842

Abstract

Pancreatic cancer is one of the deadliest cancer types urgently requiring effective therapeutic strategies. Autophagy occurs in several compartments of pancreatic cancer tissue including cancer cells, cancer associated fibroblasts, and immune cells where it can be subjected to a multitude of stimulatory and inhibitory signals fine-tuning its activity. Therefore, the effects of autophagy on pancreatic carcinogenesis and progression differ in a stage and context dependent manner. In the initiation stage autophagy hinders development of preneoplastic lesions; in the progression stage however, autophagy promotes tumor growth. This double-edged action of autophagy makes it a hard therapeutic target. Indeed, autophagy inhibitors have not yet shown survival improvements in clinical trials, indicating a need for better evaluation of existing results and smarter targeting techniques. Clearly, the role of autophagy in pancreatic cancer is complex and many aspects have to be considered when moving from the bench to the bedside. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Pancreatic Cancer)

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16 pages, 639 KiB

Open AccessReview

The Galectin Family as Molecular Targets: Hopes for Defeating Pancreatic Cancer

by Noemí Manero-Rupérez, Neus Martínez-Bosch, Luis E. Barranco, Laura Visa and Pilar Navarro

Cells 2020, 9(3), 689; https://doi.org/10.3390/cells9030689 - 11 Mar 2020

Cited by 25 | Viewed by 4670

Abstract

Galectins are a family of proteins that bind β-galactose residues through a highly conserved carbohydrate recognition domain. They regulate several important biological functions, including cell proliferation, adhesion, migration, and invasion, and play critical roles during embryonic development and cell differentiation. In adults, different galectin members are expressed depending on the tissue type and can be altered during pathological processes. Numerous reports have shown the involvement of galectins in diseases, mostly inflammation and cancer. Here, we review the state-of-the-art of the role that different galectin family members play in pancreatic cancer. This tumor is predicted to become the second leading cause of cancer-related deaths in the next decade as there is still no effective treatment nor accurate diagnosis for it. We also discuss the possible translation of recent results about galectin expression and functions in pancreatic cancer into clinical interventions (i.e., diagnosis, prediction of prognosis and/or therapy) for this fatal disease. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Pancreatic Cancer)

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34 pages, 956 KiB

Open AccessReview

From Genetic Alterations to Tumor Microenvironment: The Ariadne’s String in Pancreatic Cancer

by Chiara Bazzichetto, Fabiana Conciatori, Claudio Luchini, Francesca Simionato, Raffaela Santoro, Vanja Vaccaro, Vincenzo Corbo, Italia Falcone, Gianluigi Ferretti, Francesco Cognetti, Davide Melisi, Aldo Scarpa, Ludovica Ciuffreda and Michele Milella

Cells 2020, 9(2), 309; https://doi.org/10.3390/cells9020309 - 28 Jan 2020

Cited by 23 | Viewed by 4706

Abstract

The threatening notoriety of pancreatic cancer mainly arises from its negligible early diagnosis, highly aggressive progression, failure of conventional therapeutic options and consequent very poor prognosis. The most important driver genes of pancreatic cancer are the oncogene KRAS and the tumor suppressors TP53, CDKN2A, and SMAD4. Although the presence of few drivers, several signaling pathways are involved in the oncogenesis of this cancer type, some of them with promising targets for precision oncology. Pancreatic cancer is recognized as one of immunosuppressive phenotype cancer: it is characterized by a fibrotic-desmoplastic stroma, in which there is an intensive cross-talk between several cellular (e.g., fibroblasts, myeloid cells, lymphocytes, endothelial, and myeloid cells) and acellular (collagen, fibronectin, and soluble factors) components. In this review; we aim to describe the current knowledge of the genetic/biological landscape of pancreatic cancer and the composition of its tumor microenvironment; in order to better direct in the intrinsic labyrinth of this complex tumor type. Indeed; disentangling the genetic and molecular characteristics of cancer cells and the environment in which they evolve may represent the crucial step towards more effective therapeutic strategies Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Pancreatic Cancer)

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9 pages, 1366 KiB

Open AccessReview

Targeting the Stress-Induced Protein NUPR1 to Treat Pancreatic Adenocarcinoma

by Patricia Santofimia-Castaño, Yi Xia, Ling Peng, Adrián Velázquez-Campoy, Olga Abián, Wenjun Lan, Gwen Lomberk, Raul Urrutia, Bruno Rizzuti, Philippe Soubeyran, José Luis Neira and Juan Iovanna

Cells 2019, 8(11), 1453; https://doi.org/10.3390/cells8111453 - 17 Nov 2019

Cited by 29 | Viewed by 4997

Abstract

Cancer cells activate stress-response mechanisms to adapt themselves to a variety of stressful conditions. Among these protective mechanisms, those controlled by the stress-induced nuclear protein 1 (NUPR1) belong to the most conserved ones. NUPR1 is an 82-residue-long, monomeric, basic and intrinsically disordered protein (IDP), which was found to be invariably overexpressed in some, if not all, cancer tissues. Remarkably, we and others have previously showed that genetic inactivation of the Nupr1 gene antagonizes the growth of pancreatic cancer as well as several other tumors. With the use of a multidisciplinary strategy by combining biophysical, biochemical, bioinformatic, and biological approaches, a trifluoperazine-derived compound, named ZZW-115, has been identified as an inhibitor of the NUPR1 functions. The anticancer activity of the ZZW-115 was first validated on a large panel of cancer cells. Furthermore, ZZW-115 produced a dose-dependent tumor regression of the tumor size in xenografted mice. Mechanistically, we have demonstrated that NUPR1 binds to several importins. Because ZZW-115 binds NUPR1 through the region around the amino acid Thr68, which is located into the nuclear location signal (NLS) region of the protein, we demonstrated that treatment with ZZW-115 inhibits completely the translocation of NUPR1 from the cytoplasm to the nucleus by competing with importins. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Pancreatic Cancer)

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