Targeting Phosphatases and Kinases: How to Checkmate Cancer

Metastatic disease represents the major cause of death in oncologic patients worldwide. Accumulating evidence have highlighted the relevance of a small population of cancer cells, named cancer stem cells (CSCs), in the resistance to therapies, as well as cancer recurrence and metastasis. Standard anti-cancer treatments are not always conclusively curative, posing an urgent need to discover new targets for an effective therapy. Kinases and phosphatases are implicated in many cellular processes, such as proliferation, differentiation and oncogenic transformation. These proteins are crucial regulators of intracellular signaling pathways mediating multiple cellular activities. Therefore, alterations in kinases and phosphatases functionality is a hallmark of cancer. Notwithstanding the role of kinases and phosphatases in cancer has been widely investigated, their aberrant activation in the compartment of CSCs is nowadays being explored as new potential Achille’s heel to strike. Here, we provide a comprehensive overview of the major protein kinases and phosphatases pathways by which CSCs can evade normal physiological constraints on survival, growth, and invasion. Moreover, we discuss the potential of inhibitors of these proteins in counteracting CSCs expansion during cancer development and progression.

Download Full-text

Pivotal Role of Iron Homeostasis in the Induction of Mitochondrial Apoptosis by 6-Gingerol Through PTEN Regulated PD-L1 Expression in Embryonic Cancer Cells

Frontiers in Oncology ◽

10.3389/fonc.2021.781720 ◽

2021 ◽

Vol 11 ◽

Author(s):

Nipin Sp ◽

Dong Young Kang ◽

Eun Seong Jo ◽

Jin-Moo Lee ◽

Se Won Bae ◽

...

Keyword(s):

Cell Death ◽

Iron Homeostasis ◽

Reactive Oxygen Species Generation ◽

Cancer Recurrence ◽

Cancer Type ◽

Molecular Signaling ◽

Cellular Processes ◽

P53 Signaling ◽

Cycle Arrest ◽

Anti Cancer

Embryonic cancer stem cells (CSCs) can differentiate into any cancer type. Targeting CSCs with natural compounds is a promising approach as it suppresses cancer recurrence with fewer adverse effects. 6-Gingerol is an active component of ginger, which exhibits well-known anti-cancer activities. This study determined the mechanistic aspects of cell death induction by 6-gingerol. To analyze cellular processes, we used Western blot and real-time qPCR for molecular signaling studies and conducted flow cytometry. Our results suggested an inhibition of CSC marker expression and Wnt/β-catenin signaling by 6-gingerol in NCCIT and NTERA-2 cells. 6-Gingerol induced reactive oxygen species generation, the DNA damage response, cell cycle arrest, and the intrinsic pathway of apoptosis in embryonic CSCs. Furthermore, 6-gingerol inhibited iron metabolism and induced PTEN, which both played vital roles in the induction of cell death. The activation of PTEN resulted in the inhibition of PD-L1 expression through PI3K/AKT/p53 signaling. The induction of PTEN also mediated the downregulation of microRNAs miR-20b, miR-21, and miR-130b to result in PD-L1 suppression by 6-gingerol. Hence, 6-gingerol may be a promising candidate to target CSCs by regulating PTEN-mediated PD-L1 expression.

Download Full-text

ERK: A Double-Edged Sword in Cancer. ERK-Dependent Apoptosis as a Potential Therapeutic Strategy for Cancer

Cells ◽

10.3390/cells10102509 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2509

Author(s):

Reiko Sugiura ◽

Ryosuke Satoh ◽

Teruaki Takasaki

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Tumor Cell Death ◽

Cancer Treatments ◽

Erk Activation ◽

Cellular Processes ◽

Dual Specificity ◽

Anti Cancer ◽

Dual Specificity Phosphatases

The RAF/MEK/ERK signaling pathway regulates diverse cellular processes as exemplified by cell proliferation, differentiation, motility, and survival. Activation of ERK1/2 generally promotes cell proliferation, and its deregulated activity is a hallmark of many cancers. Therefore, components and regulators of the ERK pathway are considered potential therapeutic targets for cancer, and inhibitors of this pathway, including some MEK and BRAF inhibitors, are already being used in the clinic. Notably, ERK1/2 kinases also have pro-apoptotic functions under certain conditions and enhanced ERK1/2 signaling can cause tumor cell death. Although the repertoire of the compounds which mediate ERK activation and apoptosis is expanding, and various anti-cancer compounds induce ERK activation while exerting their anti-proliferative effects, the mechanisms underlying ERK1/2-mediated cell death are still vague. Recent studies highlight the importance of dual-specificity phosphatases (DUSPs) in determining the pro- versus anti-apoptotic function of ERK in cancer. In this review, we will summarize the recent major findings in understanding the role of ERK in apoptosis, focusing on the major compounds mediating ERK-dependent apoptosis. Studies that further define the molecular targets of these compounds relevant to cell death will be essential to harnessing these compounds for developing effective cancer treatments.

Download Full-text

Platform Study of Belantamab Mafodotin as Monotherapy and in Combination With Anti-cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (DREAMM 5)

Case Medical Research ◽

10.31525/ct1-nct04126200 ◽

2019 ◽

Author(s):

Keyword(s):

Multiple Myeloma ◽

Cancer Treatments ◽

Refractory Multiple Myeloma ◽

Anti Cancer

Download Full-text

Potential of Mesenchymal Stem Cells in Anti-Cancer Therapies

Current Stem Cell Research & Therapy ◽

10.2174/1574888x15666200310171547 ◽

2020 ◽

Vol 15 (6) ◽

pp. 482-491 ◽

Cited By ~ 1

Author(s):

Milena Kostadinova ◽

Milena Mourdjeva

Keyword(s):

Cancer Cells ◽

Small Population ◽

Tumor Formation ◽

Bioactive Molecules ◽

Cancer Therapies ◽

New Methods ◽

Cycle Arrest ◽

Anti Cancer ◽

Blocking Mechanisms

Mesenchymal stem/stromal cells (MSCs) are localized throughout the adult body as a small population in the stroma of the tissue concerned. In injury, tissue damage, or tumor formation, they are activated and leave their niche to migrate to the site of injury, where they release a plethora of growth factors, cytokines, and other bioactive molecules. With the accumulation of data about the interaction between MSCs and tumor cells, the dualistic role of MSCs remains unclear. However, a large number of studies have demonstrated the natural anti-tumor properties inherent in MSCs, so this is the basis for intensive research for new methods using MSCs as a tool to suppress cancer cell development. This review focuses specifically on advanced approaches in modifying MSCs to become a powerful, precision- targeted tool for killing cancer cells, but not normal healthy cells. Suppression of tumor growth by MSCs can be accomplished by inducing apoptosis or cell cycle arrest, suppressing tumor angiogenesis, or blocking mechanisms mediating metastasis. In addition, the chemosensitivity of cancer cells may be increased so that the dose of the chemotherapeutic agent used could be significantly reduced.

Download Full-text

Circadian rhythms, sleep, and anti-cancer treatments

10.1093/oso/9780198778240.003.0016 ◽

2018 ◽

Author(s):

Pasquale F. Innominato ◽

David Spiegel

Keyword(s):

Quality Of Life ◽

Circadian Rhythms ◽

Biological Functions ◽

Cancer Treatments ◽

Anti Cancer ◽

Timing System ◽

Physical Wellbeing ◽

Circadian Timing System ◽

Chemotherapy Agents

The circadian timing system temporally regulates biological functions relevant for psycho-physical wellbeing, spanning all the systems related to health. Hence, disruption of circadian rhythms, along with sleep cycles, is associated with the development of several diseases, including cancer. Moreover, altered circadian and sleep functions negatively impact on cancer patients’ quality of life and survival, above and beyond known determinants of outcome. This alteration can occur as a consequence of cancer, but also of anti-cancer treatments. Indeed, circadian rhythms govern also the ability of detoxifying chemotherapy agents across the 24 hours. Hence, adapting chemotherapy delivery to the molecular oscillations in relevant drug pathways can decrease toxicity to healthy cells, while increasing the number of cancer cells killing. This chronomodulated chemotherapy approach, together with the maintenance of proper circadian function throughtout the whole disease challenge, would finally result in safer and more active anticancer treatments, and in patients experiencing better quality and quantity of life.

Download Full-text

SNF1-related protein kinase 1: the many-faced signaling hub regulating developmental plasticity in plants

Journal of Experimental Botany ◽

10.1093/jxb/erab079 ◽

2021 ◽

Author(s):

Muhammed Jamsheer K ◽

Manoj Kumar ◽

Vibha Srivastava

Keyword(s):

Protein Kinase ◽

Environmental Conditions ◽

Protein Trafficking ◽

Developmental Plasticity ◽

Inositol Phosphate ◽

Future Research ◽

Primary Metabolism ◽

Related Protein ◽

Comprehensive Overview ◽

Cellular Processes

AbstractThe Snf1-related protein kinase 1 (SnRK1) is the plant homolog of the heterotrimeric AMP-activated protein kinase/sucrose non-fermenting 1 (AMPK/Snf1), which works as a major regulator of growth under nutrient-limiting conditions in eukaryotes. Along with its conserved role as a master regulator of sugar starvation responses, SnRK1 is involved in controlling the developmental plasticity and resilience under diverse environmental conditions in plants. In this review, through mining and analyzing the interactome and phosphoproteome data of SnRK1, we are highlighting its role in fundamental cellular processes such as gene regulation, protein synthesis, primary metabolism, protein trafficking, nutrient homeostasis, and autophagy. Along with the well-characterized molecular interaction in SnRK1 signaling, our analysis highlights several unchartered regions of SnRK1 signaling in plants such as its possible communication with chromatin remodelers, histone modifiers, and inositol phosphate signaling. We also discuss potential reciprocal interactions of SnRK1 signaling with other signaling pathways and cellular processes, which could be involved in maintaining flexibility and homeostasis under different environmental conditions. Overall, this review provides a comprehensive overview of the SnRK1 signaling network in plants and suggests many novel directions for future research.

Download Full-text

Anti-Cancer Effects of Glaucarubinone in the Hepatocellular Carcinoma Cell Line Huh7 via Regulation of the Epithelial-To-Mesenchymal Transition-Associated Transcription Factor Twist1

International Journal of Molecular Sciences ◽

10.3390/ijms22041700 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1700

Author(s):

Jihye Seo ◽

Jain Ha ◽

Eunjeong Kang ◽

Haelim Yoon ◽

Sewoong Lee ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Wound Healing ◽

Transcription Factor ◽

Cell Migration ◽

Cell Line ◽

Intracellular Signaling ◽

Epithelial To Mesenchymal Transition ◽

Mesenchymal Transition ◽

Huh7 Cells ◽

Anti Cancer

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is a leading cause of cancer-related deaths. As HCC has a high mortality rate and its incidence is increasing worldwide, understanding and treating HCC are crucial for resolving major public health concerns. In the present study, wound healing screening assays were performed using natural product libraries to identify natural chemicals that can inhibit cancer cell migration. Glaucarubinone (GCB) showed a high potential for inhibiting cell migration. The anti-cancer effects of GCB were evaluated using the HCC cell line, Huh7. GCB showed anti-cancer effects, as verified by wound healing, cell migration, invasion, colony formation, and three-dimensional spheroid invasion assays. In addition, cells treated with GCB showed suppressed matrix metalloproteinase activities. Immunoblotting analyses of intracellular signaling pathways revealed that GCB regulated the levels of Twist1, a crucial transcription factor associated with epithelial-to-mesenchymal transition, and mitogen-activated protein kinase. The invasive ability of cancer cells was found to be decreased by the regulation of Twist1 protein levels. Furthermore, GCB downregulated phosphorylation of extracellular signal-regulated kinase. These results indicate that GCB exhibits anti-metastatic properties in Huh7 cells, suggesting that it could be used to treat HCC.

Download Full-text

Autoimmune Responses in Oncology: Causes and Significance

International Journal of Molecular Sciences ◽

10.3390/ijms22158030 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8030

Author(s):

Halin Bareke ◽

Pablo Juanes-Velasco ◽

Alicia Landeira-Viñuela ◽

Angela-Patricia Hernandez ◽

Juan Jesús Cruz ◽

...

Keyword(s):

Cancer Immunotherapy ◽

Protein Microarrays ◽

Cross Reactivity ◽

Fine Tuning ◽

Cancer Treatments ◽

Aberrant Expression ◽

Specificity And Sensitivity ◽

Anti Cancer ◽

Life Threatening ◽

Considerable Impact

Specific anti-tumor immune responses have proven to be pivotal in shaping tumorigenesis and tumor progression in solid cancers. These responses can also be of an autoimmune nature, and autoantibodies can sometimes be present even before the onset of clinically overt disease. Autoantibodies can be generated due to mutated gene products, aberrant expression and post-transcriptional modification of proteins, a pro-immunogenic milieu, anti-cancer treatments, cross-reactivity of tumor-specific lymphocytes, epitope spreading, and microbiota-related and genetic factors. Understanding these responses has implications for both basic and clinical immunology. Autoantibodies in solid cancers can be used for early detection of cancer as well as for biomarkers of prognosis and treatment response. High-throughput techniques such as protein microarrays make parallel detection of multiple autoantibodies for increased specificity and sensitivity feasible, affordable, and quick. Cancer immunotherapy has revolutionized cancer treatments and has made a considerable impact on reducing cancer-associated morbidity and mortality. However, immunotherapeutic interventions such as immune checkpoint inhibition can induce immune-related toxicities, which can even be life-threatening. Uncovering the reasons for treatment-induced autoimmunity can lead to fine-tuning of cancer immunotherapy approaches to evade toxic events while inducing an effective anti-tumor immune response.

Download Full-text

Precision Medicine: From “Omics” to Economics towards Data-Driven Healthcare - Time for European Transformation

Biomedicine Hub ◽

10.1159/000480117 ◽

2017 ◽

Vol 2 (Suppl. 1) ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Denis Lacombe ◽

Lifang Liu ◽

Françoise Meunier ◽

Vassilis Golfinopoulos

Keyword(s):

Drug Development ◽

Development Process ◽

Precision Oncology ◽

Drug Development Process ◽

Cancer Treatments ◽

True Value ◽

Efficient Access ◽

Funding Agencies ◽

Anti Cancer

There is room for improvement for optimally bringing the latest science to the patient while taking into account patient priorities such as quality of life. Too often, regulatory agencies, governments, and funding agencies do not stimulate the integration of research into care and vice versa. Re-engineering the drug development process is a priority, and healthcare systems are long due for transformation. On one hand, patients need efficient access to treatments, but despite precision oncology approaches, efficiently shared screening platforms for sorting patients based on the biology of their tumour for trial access are lacking and, on the other hand, the true value of cancer care is poorly addressed as central questions such as dose, scheduling, duration, and combination are not or sub-optimally addressed by registration trials. Solid evidence on those parameters could potentially lead to a rational and wiser use of anti-cancer treatments. Together, optimally targeting patient population and robust comparative effectiveness data could lead to more affordable and economically sound approaches. The drug development process and healthcare models need to be interconnected through redesigned systems taking into account the full math from drug development into affordable care.

Download Full-text