scholarly journals The Multi-Functional Calcium/Calmodulin Stimulated Protein Kinase (CaMK) Family: Emerging Targets for Anti-Cancer Therapeutic Intervention

2019 ◽  
Vol 12 (1) ◽  
pp. 8 ◽  
Author(s):  
Joshua S. Brzozowski ◽  
Kathryn A. Skelding
Keyword(s):  
Protein Kinase ◽  
Cancer Cell ◽  
Therapeutic Intervention ◽  
Cell Function ◽  
Tumour Progression ◽  
Anti Cancer ◽  
Signalling Cascades ◽  
Key Events

The importance of Ca2+ signalling in key events of cancer cell function and tumour progression, such as proliferation, migration, invasion and survival, has recently begun to be appreciated. Many cellular Ca2+-stimulated signalling cascades utilise the intermediate, calmodulin (CaM). The Ca2+/CaM complex binds and activates a variety of enzymes, including members of the multifunctional Ca2+/calmodulin-stimulated protein kinase (CaMK) family. These enzymes control a broad range of cancer-related functions in a multitude of tumour types. Herein, we explore the cancer-related functions of these kinases and discuss their potential as targets for therapeutic intervention.

scholarly journals 8-Hydroxycudraxanthone G Suppresses IL-8 Production in SP-C1 Tongue Cancer Cells

2014 ◽  
Vol 9 (1) ◽  
pp. 1934578X1400900
Author(s):  
Arlette S. Setiawan ◽  
Roosje R. Oewen ◽  
Supriatno ◽  
Willyanti Soewondo ◽  
Sidik ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Therapeutic Intervention ◽  
Tongue Cancer ◽  
Cancer Cell Line ◽  
Cancer Cell Lines ◽  
Garcinia Mangostana ◽  
Anti Cancer ◽  
Cancer Activity

Production of IL-8 primarily promotes angiogenic responses in cancer cells, which lead to favorable disease progression. Suppressing this production may, therefore, be a significant therapeutic intervention in targeting tumor angiogenesis. This study aimed to evaluate the reduction effects of xanthones in cancer cell lines. Nine known prenylated xanthones (1–9), isolated from the pericarp of Garcinia mangostana Linn (GML), were tested for their ability to suppress IL-8 (interleukin-8) of the SP-C1 (Supri's Clone 1) tongue cancer cell line. Of these compounds, 8-hydroxycudraxanthone-G (4) suppressed IL-8 within 48 hours. This is the first report of 8-hydroxycudraxanthone G suppressing the production of IL-8 (45% at 15.7 μg/mL in 48 hours). These results suggest that the prolonged suppression of IL-8 production by cancer cell lines is concerned in the anti-cancer activity of 8-hydroxycudraxanthone.

scholarly journals Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 862 ◽  
Author(s):  
Nurbubu T. Moldogazieva ◽  
Innokenty M. Mokhosoev ◽  
Alexander A. Terentiev
Keyword(s):  
Protein Kinase ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Oxidative Metabolism ◽  
Cell Metabolism ◽  
Hypoxia Inducible Factor ◽  
Anti Cancer ◽  
Liver Kinase B1 ◽  
Metabolic Heterogeneity ◽  
Amp Activated Protein Kinase

It has been long recognized that cancer cells reprogram their metabolism under hypoxia conditions due to a shift from oxidative phosphorylation (OXPHOS) to glycolysis in order to meet elevated requirements in energy and nutrients for proliferation, migration, and survival. However, data accumulated over recent years has increasingly provided evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism, even in the same tumor. This phenomenon, denoted as cancer cell metabolic plasticity or hybrid metabolism, depends on a tumor micro-environment that is highly heterogeneous and influenced by an intensity of vasculature and blood flow, oxygen concentration, and nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, and reactive oxygen species (ROS), among others. Hypoxia-inducible factor-1 (HIF-1) and AMP-activated protein kinase (AMPK) represent key modulators of a switch between reprogrammed and oxidative metabolism. The present review focuses on cross-talks between HIF-1, glucose transporters (GLUTs), and AMPK with other regulatory proteins including oncogenes such as c-Myc, p53, and KRAS; growth factor-initiated protein kinase B (PKB)/Akt, phosphatidyl-3-kinase (PI3K), and mTOR signaling pathways; and tumor suppressors such as liver kinase B1 (LKB1) and TSC1 in controlling cancer cell metabolism. The multiple switches between metabolic pathways can underlie chemo-resistance to conventional anti-cancer therapy and should be taken into account in choosing molecular targets to discover novel anti-cancer drugs.

scholarly journals High ELF4 expression in human cancers is associated with worse disease outcomes and increased resistance to anticancer drugs

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0248984
Author(s):  
Doris Kafita ◽  
Victor Daka ◽  
Panji Nkhoma ◽  
Mildred Zulu ◽  
Ephraim Zulu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Protein Kinase ◽  
Cell Lines ◽  
Cancer Cell ◽  
Mrna Levels ◽  
Cancer Drugs ◽  
Human Cancers ◽  
Disease Outcomes ◽  
Anti Cancer ◽  
Tyrosine Protein Kinase

The malignant phenotype of tumour cells is fuelled by changes in the expression of various transcription factors, including some of the well-studied proteins such as p53 and Myc. Despite significant progress made, little is known about several other transcription factors, including ELF4, and how they help shape the oncogenic processes in cancer cells. To this end, we performed a bioinformatics analysis to facilitate a detailed understanding of how the expression variations of ELF4 in human cancers are related to disease outcomes and the cancer cell drug responses. Here, using ELF4 mRNA expression data of 9,350 samples from the Cancer Genome Atlas pan-cancer project, we identify two groups of patient’s tumours: those that expressed high ELF4 transcripts and those that expressed low ELF4 transcripts across 32 different human cancers. We uncover that patients segregated into these two groups are associated with different clinical outcomes. Further, we find that tumours that express high ELF4 mRNA levels tend to be of a higher-grade, afflict a significantly older patient population and have a significantly higher mutation burden. By analysing dose-response profiles to 397 anti-cancer drugs of 612 well-characterised human cancer cell lines, we discover that cell lines that expressed high ELF4 mRNA transcript are significantly less responsive to 129 anti-cancer drugs, and only significantly more response to three drugs: dasatinib, WH-4-023, and Ponatinib, all of which remarkably target the proto-oncogene tyrosine-protein kinase SRC and tyrosine-protein kinase ABL1. Collectively our analyses have shown that, across the 32 different human cancers, the patients afflicted with tumours that overexpress ELF4 tended to have a more aggressive disease that is also is more likely more refractory to most anti-cancer drugs, a finding upon which we could devise novel categorisation of patient tumours, treatment, and prognostic strategies.

scholarly journals Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Emile P. Chen ◽  
Roy S. Song ◽  
Xueer Chen
Keyword(s):  
Protein Kinase ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Tumor ◽  
Cancer Cell Lines ◽  
Cancer Drug ◽  
Anti Cancer ◽  
Cell To Cell Variability

Abstract Background Human tumor is a complex tissue with multiple heterogeneous hypoxic regions and significant cell-to-cell variability. Due to the complexity of the disease, the explanation of why anticancer therapies fail cannot be attributed to intrinsic or acquired drug resistance alone. Furthermore, there are inconsistent reports of hypoxia-induced kinase activities in different cancer cell-lines, where increase, decreases, or no change has been observed. Thus, we asked, why are there widely contrasting results in kinase activity under hypoxia in different cancer cell-lines and how does hypoxia play a role in anti-cancer drug sensitivity? Results We took a modeling approach to address these questions by analyzing the model simulation to explain why hypoxia driven signals can have dissimilar impact on tumor growth and alter the efficacy of anti-cancer drugs. Repeated simulations with varying concentrations of biomolecules followed by decision tree analysis reveal that the highly differential effects among heterogeneous subpopulation of tumor cells could be governed by varying concentrations of just a few key biomolecules. These biomolecules include activated serine/threonine-specific protein kinases (pRAF), mitogen-activated protein kinase kinase (pMEK), protein kinase B (pAkt), or phosphoinositide-4,5-bisphosphate 3-kinase (pPI3K). Additionally, the ratio of activated extracellular signal-regulated kinases (pERK) or pAkt to its respective total was a key factor in determining the sensitivity of pERK or pAkt to hypoxia. Conclusion This work offers a mechanistic insight into how hypoxia can affect the efficacy of anti-cancer drug that targets tumor signaling and provides a framework to identify the types of tumor cells that are either sensitive or resistant to anti-cancer therapy.

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