Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells

Gaggianesi, Miriam; Mangiapane, Laura Rosa; Modica, Chiara; Pantina, Vincenzo Davide; Porcelli, Gaetana; Franco, Simone Di; Iacono, Melania Lo; D'Accardo, Caterina; Verona, Francesco; Pillitteri, Irene; Turdo, Alice; Veschi, Veronica; Brancato, Ornella Roberta; Muratore, Giampaolo; Pistone, Giuseppe; Bongiorno, Maria Rita; Todaro, Matilde; Maria, Ruggero De; Stassi, Giorgio

doi:10.3390/cancers14030673

Cited by 4 publications

(3 citation statements)

References 55 publications

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“…Gaggianesi et al. demonstrated that dual indirect targeting of CD44 and MYC in CRC stem cells, using PI3K and CDK inhibitors, reduces the survival and clonogenic activity of cancer stem cells, regardless of the mutational background ( 59 ). Similarly, MIF overexpression leads to excessive signaling through CD74 surface receptor and formation of complex with CD44 that initiates the ERK/MAPK signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Differential gene expression of immunity and inflammation genes in colorectal cancer using targeted RNA sequencing

Holubekova,

Loderer,

Grendar

et al. 2023

Front. Oncol.

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IntroductionColorectal cancer (CRC) is a heterogeneous disease caused by molecular changes, as driver mutations, gene methylations, etc., and influenced by tumor microenvironment (TME) pervaded with immune cells with both pro- and anti-tumor effects. The studying of interactions between the immune system (IS) and the TME is important for developing effective immunotherapeutic strategies for CRC. In our study, we focused on the analysis of expression profiles of inflammatory and immune-relevant genes to identify aberrant signaling pathways included in carcinogenesis, metastatic potential of tumors, and association of Kirsten rat sarcoma virus (KRAS) gene mutation.MethodsA total of 91 patients were enrolled in the study. Using NGS, differential gene expression analysis of 11 tumor samples and 11 matching non-tumor controls was carried out by applying a targeted RNA panel for inflammation and immunity genes containing 475 target genes. The obtained data were evaluated by the CLC Genomics Workbench and R library. The significantly differentially expressed genes (DEGs) were analyzed in Reactome GSA software, and some selected DEGs were used for real-time PCR validation.ResultsAfter prioritization, the most significant differences in gene expression were shown by the genes TNFRSF4, IRF7, IL6R, NR3CI, EIF2AK2, MIF, CCL5, TNFSF10, CCL20, CXCL11, RIPK2, and BLNK. Validation analyses on 91 samples showed a correlation between RNA-seq data and qPCR for TNFSF10, RIPK2, and BLNK gene expression. The top differently regulated signaling pathways between the studied groups (cancer vs. control, metastatic vs. primary CRC and KRAS positive and negative CRC) belong to immune system, signal transduction, disease, gene expression, DNA repair, and programmed cell death.ConclusionAnalyzed data suggest the changes at more levels of CRC carcinogenesis, including surface receptors of epithelial or immune cells, its signal transduction pathways, programmed cell death modifications, alterations in DNA repair machinery, and cell cycle control leading to uncontrolled proliferation. This study indicates only basic molecular pathways that enabled the formation of metastatic cancer stem cells and may contribute to clarifying the function of the IS in the TME of CRC. A precise identification of signaling pathways responsible for CRC may help in the selection of personalized pharmacological treatment.

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Section: Discussionmentioning

confidence: 99%

Differential gene expression of immunity and inflammation genes in colorectal cancer using targeted RNA sequencing

Holubekova,

Loderer,

Grendar

et al. 2023

Front. Oncol.

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“…For example, Gaggianesi et al. (2022) ( 44 ) demonstrated that tumor microenvironmental cytokines promote CD44v6 expression in CRC stem cells, conferring resistance to standard anti-tumor therapeutic options, whereas Wang et al. (2019) ( 45 ) found that the downregulation of CD44v6 augments chemosensitivity of CRC cells in vitro .…”

Section: Cd44 Alternative Splicing As a Source Of Taasmentioning

confidence: 99%

CD44v6, STn & O-GD2: promising tumor associated antigens paving the way for new targeted cancer therapies

Lodewijk,

Dueñas,

Paramio

et al. 2023

Front. Immunol.

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Targeted therapies are the state of the art in oncology today, and every year new Tumor-associated antigens (TAAs) are developed for preclinical research and clinical trials, but few of them really change the therapeutic scenario. Difficulties, either to find antigens that are solely expressed in tumors or the generation of good binders to these antigens, represent a major bottleneck. Specialized cellular mechanisms, such as differential splicing and glycosylation processes, are a good source of neo-antigen expression. Changes in these processes generate surface proteins that, instead of showing decreased or increased antigen expression driven by enhanced mRNA processing, are aberrant in nature and therefore more specific targets to elicit a precise anti-tumor therapy. Here, we present promising TAAs demonstrated to be potential targets for cancer monitoring, targeted therapy and the generation of new immunotherapy tools, such as recombinant antibodies and chimeric antigen receptor (CAR) T cell (CAR-T) or Chimeric Antigen Receptor-Engineered Natural Killer (CAR-NK) for specific tumor killing, in a wide variety of tumor types. Specifically, this review is a detailed update on TAAs CD44v6, STn and O-GD2, describing their origin as well as their current and potential use as disease biomarker and therapeutic target in a diversity of tumor types.

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“…When PI3K is activated in response to a wide range of stimuli, it triggers a cascade of second messengers, leading to the activation of Akt kinase, which inhibits both GSK-3α and GSK-3β through reversible phosphorylation at S21 and S9, respectively, derepressing GSK-3 substrates [146]. Blocking PI3K releases GSK from Akt-mediated inhibition, promoting T58 Myc phosphorylation and its subsequent degradation [147][148][149]. The remarkable participation of GSK-3 in a wide range of cellular processes makes this kinase an interesting pharmacological target.…”

Section: Gsk-3mentioning

confidence: 99%

When Just One Phosphate Is One Too Many: The Multifaceted Interplay between Myc and Kinases

Boi

Rubini

Breccia

et al. 2023

IJMS

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Myc transcription factors are key regulators of many cellular processes, with Myc target genes crucially implicated in the management of cell proliferation and stem pluripotency, energy metabolism, protein synthesis, angiogenesis, DNA damage response, and apoptosis. Given the wide involvement of Myc in cellular dynamics, it is not surprising that its overexpression is frequently associated with cancer. Noteworthy, in cancer cells where high Myc levels are maintained, the overexpression of Myc-associated kinases is often observed and required to foster tumour cells’ proliferation. A mutual interplay exists between Myc and kinases: the latter, which are Myc transcriptional targets, phosphorylate Myc, allowing its transcriptional activity, highlighting a clear regulatory loop. At the protein level, Myc activity and turnover is also tightly regulated by kinases, with a finely tuned balance between translation and rapid protein degradation. In this perspective, we focus on the cross-regulation of Myc and its associated protein kinases underlying similar and redundant mechanisms of regulation at different levels, from transcriptional to post-translational events. Furthermore, a review of the indirect effects of known kinase inhibitors on Myc provides an opportunity to identify alternative and combined therapeutic approaches for cancer treatment.

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Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells

Cited by 4 publications

References 55 publications

Differential gene expression of immunity and inflammation genes in colorectal cancer using targeted RNA sequencing

Differential gene expression of immunity and inflammation genes in colorectal cancer using targeted RNA sequencing

CD44v6, STn & O-GD2: promising tumor associated antigens paving the way for new targeted cancer therapies

When Just One Phosphate Is One Too Many: The Multifaceted Interplay between Myc and Kinases

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