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14 pages, 3185 KiB

Open AccessArticle

Cordycepin (3′dA) Induces Cell Death of AC133⁺ Leukemia Cells via Re-Expression of WIF1 and Down-Modulation of MYC

by Nazanin Abazari, Marta Rachele Stefanucci, Luca Emanuele Bossi, Alessandra Trojani, Roberto Cairoli and Alessandro Beghini

Cancers 2023, 15(15), 3931; https://doi.org/10.3390/cancers15153931 - 2 Aug 2023

Cited by 4 | Viewed by 1386

Abstract

Wnt/β-catenin signaling is critically required for the development and maintenance of leukemia stem cells (LSCs) in acute myeloid leukemia (AML) by constitutive activation of myeloid regeneration-related pathways. Cell-intrinsic activation of canonical Wnt signaling propagates in the nucleus by β-catenin translocation, where it induces [...] Read more.

Wnt/β-catenin signaling is critically required for the development and maintenance of leukemia stem cells (LSCs) in acute myeloid leukemia (AML) by constitutive activation of myeloid regeneration-related pathways. Cell-intrinsic activation of canonical Wnt signaling propagates in the nucleus by β-catenin translocation, where it induces expression of target oncogenes such as JUN, MYC and CCND1. As the Wnt/β−catenin pathway is now well established to be a key oncogenic signaling pathway promoting leukemic myelopoiesis, targeting it would be an effective strategy to impair LSC functionality. Although the effects of the adenosine analogue cordycepin in repressing β-catenins and destabilizing the LSC niche have been highlighted, the cellular and molecular effects on AML–LSC have not been fully clarified. In the present study, we evaluated the potency and efficacy of cordycepin, a selective repressor of Wnt/β-catenin signaling with anti-leukemia properties, on the AC133⁺ LSC fraction. Cordycepin effectively reduces cell viability of the AC133⁺ LSCs in the MUTZ−2 cell model and patient-derived cells through the induction of apoptosis. By Wnt-targeted RNA sequencing panel, we highlighted the re-expression of WIF1 and DKK1 among others, and the consequent downregulation of MYC and PROM1 (CD133) following MUTZ−2 cell exposure to increasing doses of cordycepin. Our results provide new insights into the molecular circuits involved in pharmacological inhibition mediated by cordycepin reinforcing the potential of targeting the Wnt/β-catenin and co-regulatory complexes in AML. Full article

(This article belongs to the Special Issue A Deeper Dive into Signaling Pathways in Cancers)

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20 pages, 5943 KiB

Open AccessArticle

The CBP/β-Catenin Antagonist, ICG-001, Inhibits Tumor Metastasis via Blocking of the miR-134/ITGB1 Axis-Mediated Cell Adhesion in Nasopharyngeal Carcinoma

by Luo Chen, Yiu Chun Chiang, Lai Sheung Chan, Wai Yin Chau, Maria Li Lung, Michael Kahn, Kwok Wai Lo, Nai Ki Mak and Hong Lok Lung

Cancers 2022, 14(13), 3125; https://doi.org/10.3390/cancers14133125 - 25 Jun 2022

Cited by 8 | Viewed by 2879

Abstract

Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated malignancy ranking as the 23rd most common cancer globally, while its incidence rate ranked the 9th in southeast Asia. Tumor metastasis is the dominant cause for treatment failure in NPC and metastatic NPC is yet [...] Read more.

Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated malignancy ranking as the 23rd most common cancer globally, while its incidence rate ranked the 9th in southeast Asia. Tumor metastasis is the dominant cause for treatment failure in NPC and metastatic NPC is yet incurable. The Wnt/β-catenin signaling pathway plays an important role in many processes such as cell proliferation, differentiation, epithelial–mesenchymal transition (EMT), and self-renewal of stem cells and cancer stem cells (CSCs). Both the EMT process and CSCs are believed to play a critical role in cancer metastasis. We here investigated whether the specific CBP/β-catenin Wnt antagonist, IGC-001, affects the metastasis of NPC cells. We found that ICG-001 treatment could reduce the adhesion capability of NPC cells to extracellular matrix and to capillary endothelial cells and reduce the tumor cell migration and invasion, events which are closely associated with distant metastasis. Through a screening of EMT and CSC-related microRNAs, it was found that miR-134 was consistently upregulated by ICG-001 treatment in NPC cells. Very few reports have mentioned the functional role of miR-134 in NPC, except that the expression was found to be downregulated in NPC. Transient transfection of miR-134 into NPC cells reduced their cell adhesion, migration, and invasion capability, but did not affect the growth of CSC-enriched tumor spheres. Subsequently, we found that the ICG-001-induced miR-134 expression resulting in downregulation of integrin β1 (ITGB1). Such downregulation reduced cell adhesion and migration capability, as demonstrated by siRNA-mediated knockdown of ITGB1. Direct targeting of ITGB1 by miR-134 was confirmed by the 3′-UTR luciferase assay. Lastly, using an in vivo lung metastasis assay, we showed that ICG-001 transient overexpression of miR-134 or stable overexpression of miR-134 could significantly reduce the lung metastasis of NPC cells. Taken together, we present here evidence that modulation of Wnt/β-catenin signaling pathway could inhibit the metastasis of NPC through the miR-134/ITGB1 axis. Full article

(This article belongs to the Special Issue A Deeper Dive into Signaling Pathways in Cancers)

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16 pages, 5536 KiB

Open AccessArticle

Proteomic and Transcriptomic Profiling Reveals Mitochondrial Oxidative Phosphorylation as Therapeutic Vulnerability in Androgen Receptor Pathway Active Prostate Tumors

by Caroline Xue, Eva Corey and Taranjit S. Gujral

Cancers 2022, 14(7), 1739; https://doi.org/10.3390/cancers14071739 - 29 Mar 2022

Cited by 3 | Viewed by 2595

Abstract

Metastatic prostate cancer (PC) is the second leading cause of cancer deaths in males and has limited therapeutic options. The lack of preclinical models for advanced stage PC represents one of the primary barriers in understanding the key genetic drivers of aggressive subsets, [...] Read more.

Metastatic prostate cancer (PC) is the second leading cause of cancer deaths in males and has limited therapeutic options. The lack of preclinical models for advanced stage PC represents one of the primary barriers in understanding the key genetic drivers of aggressive subsets, including androgen receptor (AR) pathway active and AR-null castration-resistant prostate cancers (CRPC). In our studies, we described a series of LuCaP patient-derived xenograft (PDX) models representing the major genomic and phenotypic features of human disease. To fully exploit the potential of these preclinical models, we carried out a comprehensive transcriptomic and proteomic profiling of 42 LuCaP PDX prostate tumors. The collected proteomic data (~6000 data points) based on 71 antibodies revealed many of the previously known molecular markers associated with AR-positive and AR-null CRPC. Genomic analysis indicated subtype-specific activation of pathways such as Wnt/beta-catenin signaling, mTOR, and oxidative phosphorylation for AR-positive CRPC and upregulation of carbohydrate metabolism and glucose metabolism for AR-null CRPC. Of these, we functionally confirmed the role of mitochondrial metabolism in AR-positive CRPC cell lines. Our data highlight how the integration of transcriptomic and proteomic approaches and PDX systems as preclinical models can potentially map the connectivity of poorly understood signaling pathways in metastatic prostate cancer. Full article

(This article belongs to the Special Issue A Deeper Dive into Signaling Pathways in Cancers)

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13 pages, 1668 KiB

Open AccessArticle

Clinical and Tumor Characteristics of Patients with High Serum Levels of Growth Differentiation Factor 15 in Advanced Pancreatic Cancer

by Hidetaka Suzuki, Shuichi Mitsunaga, Masafumi Ikeda, Takao Aoyama, Kazumi Yoshizawa, Hiroki Yoshimatsu, Norisuke Kawai, Mari Masuda, Tomofumi Miura and Atsushi Ochiai

Cancers 2021, 13(19), 4842; https://doi.org/10.3390/cancers13194842 - 28 Sep 2021

Cited by 20 | Viewed by 3138

Abstract

We aimed to evaluate the association of circulating growth differentiation factor 15 (GDF-15) with cachexia symptoms and the biological activity of advanced pancreatic cancer (APC). Treatment-naïve patients with liver metastasis of APC or with benign pancreatic disease were retrospectively analyzed. Clinical data, blood [...] Read more.

We aimed to evaluate the association of circulating growth differentiation factor 15 (GDF-15) with cachexia symptoms and the biological activity of advanced pancreatic cancer (APC). Treatment-naïve patients with liver metastasis of APC or with benign pancreatic disease were retrospectively analyzed. Clinical data, blood samples, and biopsy specimens of liver metastasis were collected prior to anti-cancer treatment. Serum GDF-15 levels and multiple protein expressions in lysates extracted from liver metastasis were measured by enzyme-linked immuno-sorbent assay and reverse-phase protein array, respectively. The cut-off for serum GDF-15 was determined as 3356.6 pg/mL, the mean plus two standard deviations for benign pancreatic disease. The high-GDF-15 group was characterized as showing low Karnofsky performance status (KPS) (p = 0.037), poor Eastern Cooperative Oncology Group performance status (ECOG-PS) (p = 0.049), severe appetite loss (p = 0.011), and high serum levels of carbohydrate antigen 19-9 (p = 0.019) and C-reactive protein (p = 0.009). Tumors of the high-GDF-15 group expressed high levels of phosphorylated (p)JNK (p = 0.007) and pAkt (p = 0.040). APC patients with high serum GDF-15 showed signatures of cachexia and activation of the signaling pathways involving Akt and JNK in the tumor. This study indicated circulating GDF-15 could be associated with cachectic symptoms in APC. Full article

(This article belongs to the Special Issue A Deeper Dive into Signaling Pathways in Cancers)

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Review

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13 pages, 1897 KiB

Open AccessReview

p53-Dependent Cytoprotective Mechanisms behind Resistance to Chemo-Radiotherapeutic Agents Used in Cancer Treatment

by Jayaraman Krishnaraj, Tatsuki Yamamoto and Rieko Ohki

Cancers 2023, 15(13), 3399; https://doi.org/10.3390/cancers15133399 - 28 Jun 2023

Cited by 5 | Viewed by 3422

Abstract

Resistance to chemoradiotherapy is the main cause of cancer treatment failure. Cancer cells, especially cancer stem cells, utilize innate cytoprotective mechanisms to protect themselves from the adverse effects of chemoradiotherapy. Here, we describe a few such mechanisms: DNA damage response (DDR), immediate early [...] Read more.

Resistance to chemoradiotherapy is the main cause of cancer treatment failure. Cancer cells, especially cancer stem cells, utilize innate cytoprotective mechanisms to protect themselves from the adverse effects of chemoradiotherapy. Here, we describe a few such mechanisms: DNA damage response (DDR), immediate early response gene 5 (IER5)/heat-shock factor 1 (HSF1) pathway, and p21/nuclear factor erythroid 2–related factor 2 (NRF2) pathway, which are regulated by the tumour suppressor p53. Upon DNA damage caused during chemoradiotherapy, p53 is recruited to the sites of DNA damage and activates various DNA repair enzymes including GADD45A, p53R2, DDB2 to repair damaged-DNA in cancer cells. In addition, the p53-IER5-HSF1 pathway protects cancer cells from proteomic stress and maintains cellular proteostasis. Further, the p53-p21-NRF2 pathway induces production of antioxidants and multidrug resistance-associated proteins to protect cancer cells from therapy-induced oxidative stress and to promote effusion of drugs from the cells. This review summarises possible roles of these p53-regulated cytoprotective mechanisms in the resistance to chemoradiotherapy. Full article

(This article belongs to the Special Issue A Deeper Dive into Signaling Pathways in Cancers)

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15 pages, 1627 KiB

Open AccessReview

Golgi-Targeting Anticancer Natural Products

by Myat Nyein Khine and Kaori Sakurai

Cancers 2023, 15(7), 2086; https://doi.org/10.3390/cancers15072086 - 31 Mar 2023

Cited by 6 | Viewed by 3019

Abstract

The Golgi apparatus plays an important role in maintaining cell homeostasis by serving as a biosynthetic center for glycans, lipids and post-translationally modified proteins and as a sorting center for vesicular transport of proteins to specific destinations. Moreover, it provides a signaling hub [...] Read more.

The Golgi apparatus plays an important role in maintaining cell homeostasis by serving as a biosynthetic center for glycans, lipids and post-translationally modified proteins and as a sorting center for vesicular transport of proteins to specific destinations. Moreover, it provides a signaling hub that facilitates not only membrane trafficking processes but also cellular response pathways to various types of stresses. Altered signaling at the Golgi apparatus has emerged as a key regulator of tumor growth and survival. Among the small molecules that can specifically perturb or modulate Golgi proteins and organization, natural products with anticancer property have been identified as powerful chemical probes in deciphering Golgi-related pathways and, in particular, recently described Golgi stress response pathways. In this review, we highlight a set of Golgi-targeting natural products that enabled the characterization of the Golgi-mediated signaling events leading to cancer cell death and discuss the potential for selectively exploiting these pathways for the development of novel chemotherapeutic agents. Full article

(This article belongs to the Special Issue A Deeper Dive into Signaling Pathways in Cancers)

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15 pages, 1057 KiB

Open AccessReview

Receptor Tyrosine Kinases Amplified in Diffuse-Type Gastric Carcinoma: Potential Targeted Therapies and Novel Downstream Effectors

by Hideki Yamaguchi, Yuko Nagamura and Makoto Miyazaki

Cancers 2022, 14(15), 3750; https://doi.org/10.3390/cancers14153750 - 1 Aug 2022

Cited by 4 | Viewed by 4636

Abstract

Gastric cancer (GC) is a major cause of cancer-related death worldwide. Patients with an aggressive subtype of GC, known as diffuse-type gastric carcinoma (DGC), have extremely poor prognoses. DGC is characterized by rapid infiltrative growth, massive desmoplastic stroma, frequent peritoneal metastasis, and high [...] Read more.

Gastric cancer (GC) is a major cause of cancer-related death worldwide. Patients with an aggressive subtype of GC, known as diffuse-type gastric carcinoma (DGC), have extremely poor prognoses. DGC is characterized by rapid infiltrative growth, massive desmoplastic stroma, frequent peritoneal metastasis, and high probability of recurrence. These clinical features and progression patterns of DGC substantially differ from those of other GC subtypes, suggesting the existence of specific oncogenic signals. The importance of gene amplification and the resulting aberrant activation of receptor tyrosine kinase (RTK) signaling in the malignant progression of DGC is becoming apparent. Here, we review the characteristics of RTK gene amplification in DGC and its importance in peritoneal metastasis. These insights may potentially lead to new targeted therapeutics. Full article

(This article belongs to the Special Issue A Deeper Dive into Signaling Pathways in Cancers)

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18 pages, 1354 KiB

Open AccessReview

Insights into the Possible Molecular Mechanisms of Resistance to PARP Inhibitors

by Claudia Piombino and Laura Cortesi

Cancers 2022, 14(11), 2804; https://doi.org/10.3390/cancers14112804 - 5 Jun 2022

Cited by 9 | Viewed by 3939

Abstract

PARP1 enzyme plays an important role in DNA damage recognition and signalling. PARP inhibitors are approved in breast, ovarian, pancreatic, and prostate cancers harbouring a pathogenic variant in BRCA1 or BRCA2, where PARP1 inhibition results mainly in synthetic lethality in cells with [...] Read more.

PARP1 enzyme plays an important role in DNA damage recognition and signalling. PARP inhibitors are approved in breast, ovarian, pancreatic, and prostate cancers harbouring a pathogenic variant in BRCA1 or BRCA2, where PARP1 inhibition results mainly in synthetic lethality in cells with impaired homologous recombination. However, the increasingly wide use of PARP inhibitors in clinical practice has highlighted the problem of resistance to therapy. Several different mechanisms of resistance have been proposed, although only the acquisition of secondary mutations in BRCA1/2 has been clinically proved. The aim of this review is to outline the key molecular findings that could explain the development of primary or secondary resistance to PARP inhibitors, analysing the complex interactions between PARP1, cell cycle regulation, PI3K/AKT signalling, response to stress replication, homologous recombination, and other DNA damage repair pathways in the setting of BRCA1/2 mutated cancers. Full article

(This article belongs to the Special Issue A Deeper Dive into Signaling Pathways in Cancers)

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