Targeting Signaling Networks for Cancer Therapy

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15 pages, 290 KiB

Open AccessArticle

Genetic Variants in the Mitochondrial Thymidylate Biosynthesis Pathway Increase Colorectal Cancer Risk

by Entesar M. Arrait, Ayat B. Al-Ghafari and Huda A. Al Doghaither

Curr. Oncol. 2023, 30(9), 8039-8053; https://doi.org/10.3390/curroncol30090583 - 30 Aug 2023

Cited by 2 | Viewed by 1492

Abstract

We assess the contributions of genetic variants for the enzymes involved in capecitabine metabolism to colorectal cancer (CRC) development risk. In this case-control study, DNA samples were collected from 66 patients (King Abdulaziz University Hospital) and 65 controls (King Fahad General Hospital) between April and November 2022 to be used in PCR-RFLP. The chi-square (χ²) test at a significance level of p ˂ 0.05 was used to estimate genotype and allele frequencies. The Lys27Gln variant of cytidine deaminase (CDA) showed a risk ratio (RR) of 1.47 for heterozygous (AC) carriers, with genotype distributions for patients (χ² = 1.97) and controls (χ² = 14.7). Homozygous (AA) Ala70Thr carriers demonstrated a three-fold higher risk, with genotype distributions for patients (χ² = 3.85) and controls (χ² = 4.23). Genotype distributions of the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T variant for patients were (χ² = 22.43) and for controls were (χ² = 0.07); for the MTHFR A1298C variant, they were (χ² = 54.44) for patients and (χ² = 4.58) for controls. Heterozygous (AC) carriers of the A1298C variant demonstrated highly significant protection against CRC development (RR = 0.2, p = 0.001), while a two-fold higher risk for CRC was estimated for homozygous genotype (CC) carriers. In conclusion, the heterozygous genotype of CDA Lys27Gln, the homozygous genotype of CDA Ala70Thr, and the homozygous genotype of MTHFR A1298C were associated with CRC development risk. The heterozygous genotype of MTHFR A1298C variant provided highly significant protection against CRC development. Further examinations using a larger population size are needed to reliably confirm our findings. Full article

(This article belongs to the Topic Targeting Signaling Networks for Cancer Therapy)

19 pages, 698 KiB

Open AccessReview

The Role of mTOR Inhibitors after Liver Transplantation for Hepatocellular Carcinoma

by Letizia Todeschini, Luca Cristin, Alessandro Martinino, Amelia Mattia, Salvatore Agnes and Francesco Giovinazzo

Curr. Oncol. 2023, 30(6), 5574-5592; https://doi.org/10.3390/curroncol30060421 - 9 Jun 2023

Cited by 9 | Viewed by 3609

Abstract

Liver transplantation is a treatment option for nonresectable patients with early-stage HCC, with more significant advantages when Milan criteria are fulfilled. An immunosuppressive regimen is required to reduce the risk of graft rejection after transplantation, and CNIs represent the drugs of choice in this setting. However, their inhibitory effect on T-cell activity accounts for a higher risk of tumour regrowth. mTOR inhibitors (mTORi) have been introduced as an alternative immunosuppressive approach to conventional CNI-based regimens to address both immunosuppression and cancer control. The PI3K-AKT-mTOR signalling pathway regulates protein translation, cell growth, and metabolism, and the pathway is frequently deregulated in human tumours. Several studies have suggested the role of mTORi in reducing HCC progression after LT, accounting for a lower recurrence rate. Furthermore, mTOR immunosuppression controls the renal damage associated with CNI exposure. Conversion to mTOR inhibitors is associated with stabilizing and recovering renal dysfunction, suggesting an essential renoprotective effect. Limitations in this therapeutic approach are related to their negative impact on lipid and glucose metabolism as well as on proteinuria development and wound healing. This review aims to summarize the roles of mTORi in managing patients with HCC undergoing LT. Strategies to overcome common adverse effects are also proposed. Full article

(This article belongs to the Topic Targeting Signaling Networks for Cancer Therapy)

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23 pages, 2644 KiB

Open AccessReview

Tumor-Suppressive Functions of the Aryl Hydrocarbon Receptor (AhR) and AhR as a Therapeutic Target in Cancer

by Daniel J. Elson and Siva K. Kolluri

Biology 2023, 12(4), 526; https://doi.org/10.3390/biology12040526 - 30 Mar 2023

Cited by 23 | Viewed by 4667

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in regulating a wide range of biological responses. A diverse array of xenobiotics and endogenous small molecules bind to the receptor and drive unique phenotypic responses. Due in part to its role in mediating toxic responses to environmental pollutants, AhR activation has not been traditionally viewed as a viable therapeutic approach. Nonetheless, the expression and activation of AhR can inhibit the proliferation, migration, and survival of cancer cells, and many clinically approved drugs transcriptionally activate AhR. Identification of novel select modulators of AhR-regulated transcription that promote tumor suppression is an active area of investigation. The development of AhR-targeted anticancer agents requires a thorough understanding of the molecular mechanisms driving tumor suppression. Here, we summarized the tumor-suppressive mechanisms regulated by AhR with an emphasis on the endogenous functions of the receptor in opposing carcinogenesis. In multiple different cancer models, the deletion of AhR promotes increased tumorigenesis, but a precise understanding of the molecular cues and the genetic targets of AhR involved in this process is lacking. The intent of this review was to synthesize the evidence supporting AhR-dependent tumor suppression and distill insights for development of AhR-targeted cancer therapeutics. Full article

(This article belongs to the Topic Targeting Signaling Networks for Cancer Therapy)

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22 pages, 4741 KiB

Open AccessArticle

Inhibitors of the Oncogenic PA2G4-MYCN Protein-Protein Interface

by Hassina Massudi, Jie-Si Luo, Jessica K. Holien, Satyanarayana Gadde, Sukriti Krishan, Mika Herath, Jessica Koach, Brendan W. Stevenson, Michael A. Gorman, Pooja Venkat, Chelsea Mayoh, Xue-Qun Luo, Michael W. Parker, Belamy B. Cheung and Glenn M. Marshall

Cancers 2023, 15(6), 1822; https://doi.org/10.3390/cancers15061822 - 17 Mar 2023

Cited by 1 | Viewed by 2742

Abstract

MYCN is a major oncogenic driver for neuroblastoma tumorigenesis, yet there are no direct MYCN inhibitors. We have previously identified PA2G4 as a direct protein-binding partner of MYCN and drive neuroblastoma tumorigenesis. A small molecule known to bind PA2G4, WS6, significantly decreased tumorigenicity in TH-MYCN neuroblastoma mice, along with the inhibition of PA2G4 and MYCN interactions. Here, we identified a number of novel WS6 analogues, with 80% structural similarity, and used surface plasmon resonance assays to determine their binding affinity. Analogues #5333 and #5338 showed direct binding towards human recombinant PA2G4. Importantly, #5333 and #5338 demonstrated a 70-fold lower toxicity for normal human myofibroblasts compared to WS6. Structure-activity relationship analysis showed that a 2,3 dimethylphenol was the most suitable substituent at the R¹ position. Replacing the trifluoromethyl group on the phenyl ring at the R² position, with a bromine or hydrogen atom, increased the difference between efficacy against neuroblastoma cells and normal myofibroblast toxicity. The WS6 analogues inhibited neuroblastoma cell phenotype in vitro, in part through effects on apoptosis, while their anti-cancer effects required both PA2G4 and MYCN expression. Collectively, chemical inhibition of PA2G4-MYCN binding by WS6 analogues represents a first-in-class drug discovery which may have implications for other MYCN-driven cancers. Full article

(This article belongs to the Topic Targeting Signaling Networks for Cancer Therapy)

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16 pages, 1194 KiB

Open AccessArticle

High Tumor Mutation Burden Is Associated with Poor Clinical Outcome in EGFR-Mutated Lung Adenocarcinomas Treated with Targeted Therapy

by Ji-Youn Sung, Dong-Won Park and Seung-Hyeun Lee

Biomedicines 2022, 10(9), 2109; https://doi.org/10.3390/biomedicines10092109 - 29 Aug 2022

Cited by 1 | Viewed by 2399

Abstract

This study aimed to determine the association between TMB and treatment outcomes in patients with epidermal growth factor receptor (EGFR)-mutated lung cancer that were treated with tyrosine kinase inhibitors (TKIs). The TMB was assessed using a 409-gene targeted next-generation sequencing panel. We compared the response rate (RR), progression-free survival (PFS), overall survival (OS), and frequency of secondary T790M mutations among the different TMB groups. The median TMB of the study population (n = 88) was 3.36/megabases. We divided 52 (59%) and 36 (41%) patients into the low and high TMB groups, respectively. A high TMB level was significantly associated with liver metastasis and more advanced stage (all p < 0.05). RR was significantly lower in the high TMB group than that of the low TMB group (50.0% vs. 80.7%, all p = 0.0384). In multivariate analysis, high TMB was independently associated with a shorter PFS (hazard ratio [HR] = 1.80, p = 0.0427) and shorter OS (HR = 2.05, p = 0.0397) than that of the low TMB group. Further, high TMB was independently associated with decreased T790M mutation development. These results suggest that high TMB may be a predictive biomarker for adverse treatment outcomes and represent a patients’ subgroup warranting tailored therapeutic approaches. Full article

(This article belongs to the Topic Targeting Signaling Networks for Cancer Therapy)

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18 pages, 2256 KiB

Open AccessArticle

CD44 Depletion in Glioblastoma Cells Suppresses Growth and Stemness and Induces Senescence

by Constantinos Kolliopoulos, Mohamad Moustafa Ali, Casimiro Castillejo-Lopez, Carl-Henrik Heldin and Paraskevi Heldin

Cancers 2022, 14(15), 3747; https://doi.org/10.3390/cancers14153747 - 31 Jul 2022

Cited by 20 | Viewed by 4347

Abstract

Glioblastoma multiforme (GBM) is a lethal brain tumor, characterized by enhanced proliferation and invasion, as well as increased vascularization and chemoresistance. The expression of the hyaluronan receptor CD44 has been shown to correlate with GBM progression and poor prognosis. Here, we sought to elucidate the molecular mechanisms by which CD44 promotes GBM progression by knocking out (KO) CD44, employing CRISPR/Cas9 gene editing in U251MG cells. CD44-depleted cells exhibited an impaired proliferation rate, as shown by the decreased cell numbers, decreased Ki67-positive cell nuclei, diminished phosphorylation of CREB, and increased levels of the cell cycle inhibitor p16 compared to control cells. Furthermore, the CD44 KO cells showed decreased stemness and increased senescence, which was manifested upon serum deprivation. In stem cell-like enriched spheres, RNA-sequencing analysis of U251MG cells revealed a CD44 dependence for gene signatures related to hypoxia, the glycolytic pathway, and G2 to M phase transition. Partially similar results were obtained when cells were treated with the γ-secretase inhibitor DAPT, which inhibits CD44 cleavage and therefore inhibits the release of the intracellular domain (ICD) of CD44, suggesting that certain transcriptional responses are dependent on CD44-ICD. Interestingly, the expression of molecules involved in hyaluronan synthesis, degradation, and interacting matrix proteins, as well as of platelet-derived growth factor (PDGF) isoforms and PDGF receptors, were also deregulated in CD44 KO cells. These results were confirmed by the knockdown of CD44 in another GBM cell line, U2990. Notably, downregulation of hyaluronan synthase 2 (HAS2) impaired the hypoxia-related genes and decreased the CD44 protein levels, suggesting a CD44/hyaluronan feedback circuit contributing to GBM progression. Full article

(This article belongs to the Topic Targeting Signaling Networks for Cancer Therapy)

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16 pages, 4726 KiB

Open AccessArticle

Regulation of Interleukin-36γ/IL-36R Signaling Axis by PIN1 in Epithelial Cell Transformation and Breast Tumorigenesis

by Muna Poudel, Poshan Yugal Bhattarai, Pratikshya Shrestha and Hong Seok Choi

Cancers 2022, 14(15), 3654; https://doi.org/10.3390/cancers14153654 - 27 Jul 2022

Cited by 6 | Viewed by 2741

Abstract

Given the increasing recognition of the relationship between IL-1 cytokines, inflammation, and cancer, the significance of distinct members of the IL-1 cytokine family in the etiology of cancer has been widely researched. In the present study, we investigated the underlying mechanism of the IL-36γ/IL-36R axis during breast cancer progression, which has not yet been elucidated. Initially, we determined the effects of IL-36γ on the proliferation and epithelial cell transformation of JB6 Cl41 mouse epidermal and MCF7 human breast cancer cells using BrdU incorporation and anchorage-independent growth assays. We found that treatment with IL-36γ increased the proliferation and colony formation of JB6 Cl41 and MCF7 cells. Analysis of the mechanism underlying the neoplastic cell transformation revealed that IL-36γ induced IL-36R-mediated phosphorylation of MEK1/2, ERK1/2, JNK1/2, and c-Jun, resulting in increased c-Fos, c-Jun, and AP-1 activities in JB6 Cl41 and MCF7 cells. Furthermore, the IL-36γ-induced tumorigenic capacity of MCF7 cells was considerably enhanced by PIN1, following MEK/ERK and JNK/c-Jun signaling. Interestingly, blocking PIN1 activity using juglone suppressed the IL-36γ-induced increase in the anchorage-independent growth of 4T1 metastatic mouse breast cancer cells. Finally, in a syngeneic mouse model, IL-36γ-induced tumor growth in the breast mammary gland was significantly inhibited following PIN1 knockout. Full article

(This article belongs to the Topic Targeting Signaling Networks for Cancer Therapy)

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13 pages, 1137 KiB

Open AccessReview

N⁶-Methyladenosine RNA-Binding Protein YTHDF1 in Gastrointestinal Cancers: Function, Molecular Mechanism and Clinical Implication

by Danyu Chen, Henley Cheung, Harry Cheuk-Hay Lau, Jun Yu and Chi Chun Wong

Cancers 2022, 14(14), 3489; https://doi.org/10.3390/cancers14143489 - 18 Jul 2022

Cited by 18 | Viewed by 4445

Abstract

N⁶-methyladenosine (m⁶A) is the most abundant internal modification in eukaryotic cell mRNA, and this modification plays a key role in regulating mRNA translation, splicing, and stability. Emerging evidence implicates aberrant m⁶A as a crucial player in the occurrence and development of diseases, especially GI cancers. Among m⁶A regulators, YTHDF1 is the most abundant m⁶A reader that functionally connects m⁶A-modified mRNA to its eventual fate, mostly notably protein translation. Here, we summarized the function, molecular mechanisms, and clinical implications of YTHDF1 in GI cancers. YTHDF1 is largely upregulated in multiple GI cancer and its high expression predicts poor patient survival. In vitro and in vivo experimental evidence largely supports the role of YTDHF1 in promoting cancer initiation, progression, and metastasis, which suggests the oncogenic function of YTHDF1 in GI cancers. Besides, YTHDF1 overexpression is associated with changes in the tumor microenvironment that are favorable to tumorigenesis. Mechanistically, YTHDF1 regulates the expression of target genes by promoting translation, thereby participating in cancer-related signaling pathways. Targeting YTHDF1 holds therapeutic potential, as the overexpression of YTHDF1 is associated with tumor resistance to chemotherapy and immunotherapy. In summary, YTHDF1-mediated regulation of m⁶A modified mRNA is an actionable target and a prognostic factor for GI cancers. Full article

(This article belongs to the Topic Targeting Signaling Networks for Cancer Therapy)

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Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biology biology	3.6	5.7	2012	16.4 Days	CHF 2700
Biomedicines biomedicines	3.9	5.2	2013	14.6 Days	CHF 2600
Cancers cancers	4.5	8.0	2009	17.4 Days	CHF 2900
Current Oncology curroncol	2.8	3.3	1994	19.8 Days	CHF 2200
Onco onco	-	-	2021	27.8 Days	CHF 1000

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