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

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.

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Reevaluation of the role of LIP-1 as an ERK/MPK-1 dual specificity phosphatase in the C. elegans germline

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2113649119 ◽

2022 ◽

Vol 119 (3) ◽

pp. e2113649119

Author(s):

Debabrata Das ◽

Jacob Seemann ◽

David Greenstein ◽

Tim Schedl ◽

Swathi Arur

Keyword(s):

Failure To Rescue ◽

Gain Of Function ◽

Erk Activation ◽

C Elegans ◽

Cellular Processes ◽

Dual Specificity ◽

Extracellular Signal ◽

Dual Specificity Phosphatases ◽

Organismal Development

The fidelity of a signaling pathway depends on its tight regulation in space and time. Extracellular signal-regulated kinase (ERK) controls wide-ranging cellular processes to promote organismal development and tissue homeostasis. ERK activation depends on a reversible dual phosphorylation on the TEY motif in its active site by ERK kinase (MEK) and dephosphorylation by DUSPs (dual specificity phosphatases). LIP-1, a DUSP6/7 homolog, was proposed to function as an ERK (MPK-1) DUSP in the Caenorhabditis elegans germline primarily because of its phenotype, which morphologically mimics that of a RAS/let-60 gain-of-function mutant (i.e., small oocyte phenotype). Our investigations, however, reveal that loss of lip-1 does not lead to an increase in MPK-1 activity in vivo. Instead, we show that loss of lip-1 leads to 1) a decrease in MPK-1 phosphorylation, 2) lower MPK-1 substrate phosphorylation, 3) phenocopy of mpk-1 reduction-of-function (rather than gain-of-function) allele, and 4) a failure to rescue mpk-1–dependent germline or fertility defects. Moreover, using diverse genetic mutants, we show that the small oocyte phenotype does not correlate with increased ectopic MPK-1 activity and that ectopic increase in MPK-1 phosphorylation does not necessarily result in a small oocyte phenotype. Together, these data demonstrate that LIP-1 does not function as an MPK-1 DUSP in the C. elegans germline. Our results caution against overinterpretation of the mechanistic underpinnings of orthologous phenotypes, since they may be a result of independent mechanisms, and provide a framework for characterizing the distinct molecular targets through which LIP-1 may mediate its several germline functions.

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The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities

Cancers ◽

10.3390/cancers12082106 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2106 ◽

Cited By ~ 4

Author(s):

Jacopo Boni ◽

Carlota Rubio-Perez ◽

Nuria López-Bigas ◽

Cristina Fillat ◽

Susana de la Luna

Keyword(s):

Gene Expression ◽

Cell Death ◽

Small Molecules ◽

Clinical Implications ◽

Hallmarks Of Cancer ◽

Cellular Processes ◽

Tumor Onset ◽

Dual Specificity ◽

Cancer Initiation

DYRK (dual-specificity tyrosine-regulated kinases) are an evolutionary conserved family of protein kinases with members from yeast to humans. In humans, DYRKs are pleiotropic factors that phosphorylate a broad set of proteins involved in many different cellular processes. These include factors that have been associated with all the hallmarks of cancer, from genomic instability to increased proliferation and resistance, programmed cell death, or signaling pathways whose dysfunction is relevant to tumor onset and progression. In accordance with an involvement of DYRK kinases in the regulation of tumorigenic processes, an increasing number of research studies have been published in recent years showing either alterations of DYRK gene expression in tumor samples and/or providing evidence of DYRK-dependent mechanisms that contribute to tumor initiation and/or progression. In the present article, we will review the current understanding of the role of DYRK family members in cancer initiation and progression, providing an overview of the small molecules that act as DYRK inhibitors and discussing the clinical implications and therapeutic opportunities currently available.

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Role of Hypoxia-Mediated Autophagy in Tumor Cell Death and Survival

Cancers ◽

10.3390/cancers13030533 ◽

2021 ◽

Vol 13 (3) ◽

pp. 533

Author(s):

Rania F. Zaarour ◽

Bilal Azakir ◽

Edries Y. Hajam ◽

Husam Nawafleh ◽

Nagwa A. Zeinelabdin ◽

...

Keyword(s):

Cell Death ◽

Type I ◽

Dependent Manner ◽

Destruction Process ◽

Tumor Cell Death ◽

Complex Regulation ◽

Cancer Immunotherapies ◽

The Relationship ◽

Shed Light

Programmed cell death or type I apoptosis has been extensively studied and its contribution to the pathogenesis of disease is well established. However, autophagy functions together with apoptosis to determine the overall fate of the cell. The cross talk between this active self-destruction process and apoptosis is quite complex and contradictory as well, but it is unquestionably decisive for cell survival or cell death. Autophagy can promote tumor suppression but also tumor growth by inducing cancer-cell development and proliferation. In this review, we will discuss how autophagy reprograms tumor cells in the context of tumor hypoxic stress. We will illustrate how autophagy acts as both a suppressor and a driver of tumorigenesis through tuning survival in a context dependent manner. We also shed light on the relationship between autophagy and immune response in this complex regulation. A better understanding of the autophagy mechanisms and pathways will undoubtedly ameliorate the design of therapeutics aimed at targeting autophagy for future cancer immunotherapies.

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Apoptotic tumor-cell death in response to cell proliferation is influenced by p53 status in resected non-small cell lung cancer

Lung Cancer ◽

10.1016/s0169-5002(01)00462-7 ◽

2002 ◽

Vol 36 (1) ◽

pp. 27-32 ◽

Cited By ~ 8

Author(s):

Fumihiro Tanaka ◽

Tetsuya Takata ◽

Tomoko Yamada ◽

Kazuhiro Yanagihara ◽

Yosuke Otake ◽

...

Keyword(s):

Lung Cancer ◽

Cell Proliferation ◽

Cell Death ◽

Tumor Cell ◽

Small Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Tumor Cell Death ◽

Apoptotic Tumor Cell ◽

P53 Status

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Bcl-2 Inhibition to Overcome Resistance to Chemo- and Immunotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms19123950 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3950 ◽

Cited By ~ 27

Author(s):

Marilina García-Aranda ◽

Elisabet Pérez-Ruiz ◽

Maximino Redondo

Keyword(s):

Cancer Treatment ◽

World Health ◽

Apoptosis Resistance ◽

Hallmarks Of Cancer ◽

Cancer Treatments ◽

Over Expression ◽

Promising Strategy ◽

Anti Cancer ◽

Health Organization

Abstract: According to the World Health Organization (WHO), cancer is a leading cause of death worldwide. The identification of novel targets for cancer treatment is an area of intense work that has led Bcl-2 over-expression to be proposed as one of the hallmarks of cancer and Bcl-2 inhibition as a promising strategy for cancer treatment. In this review, we describe the different pathways related to programmed cell death, the role of Bcl-2 family members in apoptosis resistance to anti-cancer treatments, and the potential utility of Bcl-2 inhibitors to overcome resistance to chemo- and immunotherapy.

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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.

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Role of intracellular calcium concentration on tumor cell death from hyperthermia.

Oncology Reports ◽

10.3892/or.5.1.139 ◽

1998 ◽

Author(s):

Y Itagaki ◽

K Akagi ◽

M Uda ◽

Y Tanaka

Keyword(s):

Cell Death ◽

Tumor Cell ◽

Intracellular Calcium ◽

Calcium Concentration ◽

Intracellular Calcium Concentration ◽

Tumor Cell Death

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On the Anti-Cancer Effect of Cold Atmospheric Plasma and the Possible Role of Catalase-Dependent Apoptotic Pathways

Cells ◽

10.3390/cells9102330 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2330

Author(s):

Charlotta Bengtson ◽

Annemie Bogaerts

Keyword(s):

Mathematical Model ◽

Cell Death ◽

Apoptotic Cell ◽

Atmospheric Plasma ◽

Cold Atmospheric Plasma ◽

Cancer Cell Death ◽

Anti Cancer ◽

Apoptotic Pathways ◽

Cell Signaling Pathways

Cold atmospheric plasma (CAP) is a promising new agent for (selective) cancer treatment, but the underlying cause of the anti-cancer effect of CAP is not well understood yet. Among different theories and observations, one theory in particular has been postulated in great detail and consists of a very complex network of reactions that are claimed to account for the anti-cancer effect of CAP. Here, the key concept is a reactivation of two specific apoptotic cell signaling pathways through catalase inactivation caused by CAP. Thus, it is postulated that the anti-cancer effect of CAP is due to its ability to inactivate catalase, either directly or indirectly. A theoretical investigation of the proposed theory, especially the role of catalase inactivation, can contribute to the understanding of the underlying cause of the anti-cancer effect of CAP. In the present study, we develop a mathematical model to analyze the proposed catalase-dependent anti-cancer effect of CAP. Our results show that a catalase-dependent reactivation of the two apoptotic pathways of interest is unlikely to contribute to the observed anti-cancer effect of CAP. Thus, we believe that other theories of the underlying cause should be considered and evaluated to gain knowledge about the principles of CAP-induced cancer cell death.

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