The Role of CDK4 in the Pathogenesis of Pancreatic Cancer

Jiggens, Emily; Mortoglou, Maria; Grant, Guy H.; Uysal-Onganer, Pinar

doi:10.3390/healthcare9111478

Cited by 3 publications

(4 citation statements)

References 44 publications

(52 reference statements)

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“…Moreover, DDX46 also increased the JMJD6 target gene CDK4 expression. It has been revealed CDK4 was involved in the pathogenesis of PAAD [32,33]. Our study uncovered a novel pathological mechanism promoting PAAD progression.…”

Section: Discussionmentioning

confidence: 68%

Oncogenic DDX46 promotes pancreatic cancer development and gemcitabine resistance by facilitating the JMJD6/CDK4 signaling pathway

Yang,

Wang,

Wang

et al. 2024

neo

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Pancreatic cancer (PAAD) is a fatal malignancy with a poor prognosis. The treatment strategies are quite limited and gemcitabine is the canonical one, which has been proven to improve the prognosis of PAAD patients. However, the treatment efficiency of gemcitabine is far from satisfactory and remains to be further improved. DEAD-Box Helicase 46 (DDX46) is a kind of RNA helicase, which promotes multiple cancers development. However, its role in PAAD is largely unknown. In the present study, we found DDX46 was highly expressed in PAAD tissues and correlated with poor prognosis. Knockdown of DDX46 repressed PAAD cell growth in vitro and in vivo and sensitized PAAD cells to gemcitabine treatment. Mechanically, DDX46 bound to JMJD6 and promoted JMJD6/CDK4 signaling pathway. Overexpression of JMJD6 reversed the anti-tumor function of DDX46 knockdown. Our study found a novel pathological mechanism of PAAD progression and provided a potential therapeutic target to improve gemcitabine efficiency.

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Section: Discussionmentioning

confidence: 68%

Oncogenic DDX46 promotes pancreatic cancer development and gemcitabine resistance by facilitating the JMJD6/CDK4 signaling pathway

Yang,

Wang,

Wang

et al. 2024

neo

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“…Pancreatic cancer (PC), especially pancreatic ductal adenocarcinoma (PDAC), is one of the deadliest cancers with a very poor prognosis. The 5-year survival rate of patients with PC who have standard chemotherapy is less than 10% (40). Most PC harbor mutations of KRAS which is a regulating pathway of cell cycle machinery expressions and of CDKN2A, is a gene encoding p16 protein that acts as a natural cell cycle inhibitor.…”

Section: Pancreatic Cancermentioning

confidence: 99%

“…The later studies of CDK4/6 inhibitors were carried forward and they found what might provide only a modest effect if they were used as single agents (43). In addition, CDK4 expression itself could not be a good predictor for the response to CDK4/6 inhibitor (40). The anti-proliferative effects were more pronounced when CDK4/6 inhibitors were combined with a certain chemotherapy (44).…”

Section: Pancreatic Cancermentioning

confidence: 99%

Cyclin-Dependent Kinase 4/6 Inhibitors: A Potential Breakthrough Therapy for Malignancies of Gastrointestinal Tract

Zeng

Zhou

Khowtanapanich

et al. 2022

In Vivo

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Cancer is the leading cause of death worldwide for which effective treatments remain limited. This article aimed to critically review and discuss the potential of targeting cell cycle machineries as a vital tool for cancer treatment. Cyclin dependent kinase (CDK) 4/6 inhibitors were originally approved by the United State Food and Drug Administration (US FDA) for advanced-stage breast cancer treatment. The nearly double-prolonged survival time in patients who received CDK4/6 inhibitors are superior to the conventional chemotherapy or endocrine therapy alone and, thus, these medications have been designated a breakthrough therapy by the US FDA. The requirement of CDK4/6 in the progression of cancer cells, but probably dispensable in normal cells, makes CDK4/6 a popular target for cancer treatment. The effects of CDK4/6 inhibitors in cancer may also involve the tumor microenvironment in which the therapeutic effects are synergistically pronounced. These emerging roles, hence, prompt investigations regarding their therapeutic potential in other cancers, including gastrointestinal cancer. Many preclinical and clinical studies of CDK4/6 inhibitors in gastrointestinal cancers are underway and, as a result, several new potentials are gradually reported. Contrariwise, the primary effect of this drug group is arresting the cell cycle rather than inducing cell death. The efficacy of using CDK4/6 inhibitors as a single regimen in clinical practice is then limited. In this article, the effects of CDK4/6 inhibitors on the progression of gastrointestinal cancers, at both preclinical and clinical levels are reviewed. The future directions for research and the possibility of CDK4/6 inhibitors being "breakthrough therapy" for gastrointestinal cancers are also discussed.Cancer is recognized as a leading cause of death worldwide, whereas effective treatments are underway and yet to be developed for malignancies in certain organs (1). Cancer cells possess malignant hallmarks that differentiate them from their normal counterparts in the same tissues (2). The abnormality at the genetic or epigenetic levels results in cellular transformation and gain the ability to compete and invade their surrounding tissues. Limitless replication is one of the cancer hallmarks (2). Cancer cells gain this ability through various molecular mechanisms, e.g., amplification of proliferation-associated genes, autoactivation of growth signaling pathways, and the mutation of cell cycle inhibitor genes (3). Although these mechanisms benefit cancer cells to survive, it could be a double-sided sword for their survival. The requirement of unnatural overexpression of genes or proteins makes cancer cells dependent on those oncogenes and this dependency becomes their Achilles' heel. 1580

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“…Among these regulators, CDK-4 and CDK-6 play pivotal roles and are frequently dysregulated in various human cancers [7]. CDK-4 plays a crucial role in orchestrating the orderly progression of the cell cycle by binding to cyclin D to facilitate the G1/S transition [8]. The cell cycle, a highly conserved and sequential process, includes four phases: G1 (pre-DNA synthesis), S (DNA synthesis), G2 (pre-division), and M (cell division).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Proliferation and Induction of Apoptosis in Prostatic Carcinoma DU145 Cells by Polysaccharides from Yunnan Rosa roxburghii Tratt

Yang,

Chen

2024

Molecules

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Objective: This study aimed to investigate methodologies for the extraction and purification of polysaccharides from Rosa roxburghii Tratt fruits and their impact on various cellular processes in prostate cancer DU145 cells, including survival rate, migration, invasion, cell cycle, and apoptosis. Results: Compared to the control group, the polysaccharide exhibited a significant reduction in the viability, migration, and invasion rates of DU145 cells in a time- and dose-dependent manner within the polysaccharide-treated groups. Additionally, it effectively arrested the cell cycle of DU145 cells at the G0/G1 phase by downregulating the expressions of CDK-4, CDK-6, and Cyclin D1. Furthermore, it induced apoptosis by upregulating the expressions of Caspase 3, Caspase 8, Caspase 9, and BAX. Methods: Polysaccharides were extracted from Rosa roxburghii Tratt sourced from Yunnan, China. Extraction and decolorization methods were optimized using response surface methodology, based on a single-factor experiment. Polysaccharide purification was carried out using DEAE-52 cellulose and Sephadex G-100 column chromatography. The optimal dosage of R. roxburghii Tratt polysaccharide affecting DU145 cells was determined using the CCK-8 assay. Cell migration and invasion were assessed using transwell and scratch assays. Flow cytometry was employed to analyze the effects on the cell cycle and apoptosis. Western blotting and Quantitative real-time PCR were utilized to examine protein and mRNA expressions in DU145 cells, respectively. Conclusions: Rosa roxburghii Tratt polysaccharides, consisting of D-mannose, L-rhamnose, N-acetyl-D-glucosamine, D-galacturonic acid, D-glucose, D-galactcose, D-xylose, L-arabinose, and L-fucose, possess the ability to hinder DU145 cell proliferation, migration, and invasion while inducing apoptosis through the modulation of relevant protein and gene expressions.

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The Role of CDK4 in the Pathogenesis of Pancreatic Cancer

Cited by 3 publications

References 44 publications

Oncogenic DDX46 promotes pancreatic cancer development and gemcitabine resistance by facilitating the JMJD6/CDK4 signaling pathway

Oncogenic DDX46 promotes pancreatic cancer development and gemcitabine resistance by facilitating the JMJD6/CDK4 signaling pathway

Cyclin-Dependent Kinase 4/6 Inhibitors: A Potential Breakthrough Therapy for Malignancies of Gastrointestinal Tract

Inhibition of Proliferation and Induction of Apoptosis in Prostatic Carcinoma DU145 Cells by Polysaccharides from Yunnan Rosa roxburghii Tratt

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