&lt;p&gt;Effects of Atypical Protein Kinase C Inhibitor (DNDA) on Lung Cancer Proliferation and Migration by PKC-ι/FAK Ubiquitination Through the Cbl-b Pathway&lt;/p&gt;

Bommareddy, Raja Reddy; Patel, Rekha; Smalley, Tracess; Acevedo‐Duncan, Mildred

doi:10.2147/ott.s224866

Cited by 6 publications

(7 citation statements)

References 31 publications

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“…Upon treatment of non‐small‐cell lung carcinoma (NSCLC) with atypical protein kinase C (aPKCs) inhibitors, so‐called DNDA (3,4‐amino‐2,7 naphthalene disulfonic acid), DNDA interrupts the link between PKC‐ι/FAK and subsequently leads to FAK ubiquitination and degradation mediated by Cbl‐b. Finally, this process results in the induction of apoptosis in lung cells, as well as the prevention of cancer cell proliferation, migration and invasion [137]. The more elevated expression level of miR‐1323 foretells poor prognosis in lung adenocarcinoma (LUAD) and NSCLC patients, whereas enhanced expression of Cbl‐b is associated with better prognosis [138].…”

Section: Cbl‐b In Immune‐related Diseasesmentioning

confidence: 99%

E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy

Jafari

Mousavi

Shahbaz

et al. 2021

Clinical and Experimental Immunology

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Summary The distinction of self from non‐self is crucial to prevent autoreactivity and ensure protection from infectious agents and tumors. Maintaining the balance between immunity and tolerance of immune cells is strongly controlled by several sophisticated regulatory mechanisms of the immune system. Among these, the E3 ligase ubiquitin Casitas B cell lymphoma‐b (Cbl‐b) is a newly identified component in the ubiquitin‐dependent protein degradation system, which is thought to be an important negative regulator of immune cells. An update on the current knowledge and new concepts of the relevant immune homeostasis program co‐ordinated by Cbl‐b in different cell populations could pave the way for future immunomodulatory therapies of various diseases, such as autoimmune and allergic diseases, infections, cancers and other immunopathological conditions. In the present review, the latest findings are comprehensively summarized on the molecular structural basis of Cbl‐b and the suppressive signaling mechanisms of Cbl‐b in physiological and pathological immune responses, as well as its emerging potential therapeutic implications for immunotherapy in animal models and human diseases.

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Section: Cbl‐b In Immune‐related Diseasesmentioning

confidence: 99%

E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy

Jafari

Mousavi

Shahbaz

et al. 2021

Clinical and Experimental Immunology

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“…PKCι is similarly overexpressed in NSCLC tissues compared to normal lung epithelium [ 56 , 57 , 58 , 59 , 60 ]. Western blot analysis of NSCLC cell lines A549, H520, H1299, H292, ChaGo, and Sk-Mes1 showed high PKCι protein levels [ 59 , 61 ]. Overexpression of PKCι correlated with poor OS of lung adenocarcinoma patients [ 62 ].…”

Section: Expression Biological Role and Prognosis Of Protein Kinase C In Nsclcmentioning

confidence: 99%

“…Notably, a study looking at lung adenocarcinoma tissue reported increased PKCι expression in invasive lesions [ 62 ]. Pharmacological inhibition of PKCι using atypical PKC inhibitor DNDA increased the apoptosis of H1299 and A549 cells, accompanied by a decrease in pro-survival Bcl-2 and an increase in cleaved caspase-3 [ 59 ]. Additionally, PKCι regulates Bcl-x splicing, promoting survival through anti-apoptotic Bcl-x(L) expression [ 66 ].…”

Section: Expression Biological Role and Prognosis Of Protein Kinase C In Nsclcmentioning

confidence: 99%

Protein Kinase C as a Therapeutic Target in Non-Small Cell Lung Cancer

Sadeghi

Salama

Hannun

2021

IJMS

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Driver-directed therapeutics have revolutionized cancer treatment, presenting similar or better efficacy compared to traditional chemotherapy and substantially improving quality of life. Despite significant advances, targeted therapy is greatly limited by resistance acquisition, which emerges in nearly all patients receiving treatment. As a result, identifying the molecular modulators of resistance is of great interest. Recent work has implicated protein kinase C (PKC) isozymes as mediators of drug resistance in non-small cell lung cancer (NSCLC). Importantly, previous findings on PKC have implicated this family of enzymes in both tumor-promotive and tumor-suppressive biology in various tissues. Here, we review the biological role of PKC isozymes in NSCLC through extensive analysis of cell-line-based studies to better understand the rationale for PKC inhibition. PKC isoforms α, ε, η, ι, ζ upregulation has been reported in lung cancer, and overexpression correlates with worse prognosis in NSCLC patients. Most importantly, PKC isozymes have been established as mediators of resistance to tyrosine kinase inhibitors in NSCLC. Unfortunately, however, PKC-directed therapeutics have yielded unsatisfactory results, likely due to a lack of specific evaluation for PKC. To achieve satisfactory results in clinical trials, predictive biomarkers of PKC activity must be established and screened for prior to patient enrollment. Furthermore, tandem inhibition of PKC and molecular drivers may be a potential therapeutic strategy to prevent the emergence of resistance in NSCLC.

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“…The human Cbl-b gene is located on chromosome 3q11–13.1 and contains 19 exons, which is the largest of the three Cbl genes . Cbl family proteins play important roles in regulating the process of cell activation, signaling, proliferation, migration, and survival. − Interestingly enough, protein domain structure and the expression profile of Cbl-b and c-Cbl are highly semblable, but they may play different roles in term of physiological functions and immune cell signal transduction. , Currently the most intensively studied member of the Cbl family is Cbl-b. Extensive studies have indicated that Cbl-b protein, as a key negative regulator, involve C-type lectin receptor (CLR), T-cell receptor (TCR), CD28, CD40, and B-cell receptor (BCR)-mediated signaling transduction, which in turn regulates innate and adaptive immune responses. ,− Additionally, mice that knock out Cbl-b are more proned to spontaneous in vivo rejection of tumors. − Cbl-b is primarily expressed in immune cells including dendritic cells (DC), B cells and T cells. − These findings demonstrate that Cbl-b may be a promising antitumor immunotherapy target.…”

Section: Introductionmentioning

confidence: 99%

Rising Star in Immunotherapy: Development and Therapeutic Potential of Small-Molecule Inhibitors Targeting Casitas B Cell Lymphoma-b (Cbl-b)

Zhou,

Yang,

Zhang

et al. 2024

J. Med. Chem.

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Casitas B cell lymphoma-b (Cbl-b) is a vital negative regulator of TCR and BCR signaling pathways, playing a significant role in setting an appropriate threshold for the activation of T cells and controlling the tolerance of peripheral T cells via a variety of mechanisms. Overexpression of Cbl-b leads to immune hyporesponsiveness of T cells. Conversely, the deficiency of Cbl-b in T cells results in markedly increased production of IL-2, even in the lack of CD28 costimulation in vitro. And Cbl-b −/− mice spontaneously reject multifarious cancers. Therefore, Cbl-b may be associated with immune-mediated diseases, and blocking Cbl-b could be considered as a new antitumor immunotherapy strategy. In this review, the possible regulatory mechanisms and biological potential of Cbl-b for antitumor immunotherapy are summarized. Besides, the potential roles of Cbl-b in immune-mediated diseases are comprehensively discussed, with emphasis on Cbl-b immune-oncology agents in the preclinical stage and clinical trials. ■ SIGNIFICANCE • Cbl-b is a novel intracellular immune checkpoint, closely related to the development of cancers. Therefore, developing agents targeting Cbl-b is of great significance. • The lead optimization, molecular docking, and related patents research of Cbl-b inhibitors are discussed in detail from the perspective of medicinal chemistry. • The regulatory mechanism, crystal structure, and clinical progress of Cbl-b are introduced in detail, providing guidance for developing Cbl-b inhibitors with better druggability in the future.

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<p>Effects of Atypical Protein Kinase C Inhibitor (DNDA) on Lung Cancer Proliferation and Migration by PKC-ι/FAK Ubiquitination Through the Cbl-b Pathway</p>

Cited by 6 publications

References 31 publications

E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy

E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy

Protein Kinase C as a Therapeutic Target in Non-Small Cell Lung Cancer

Rising Star in Immunotherapy: Development and Therapeutic Potential of Small-Molecule Inhibitors Targeting Casitas B Cell Lymphoma-b (Cbl-b)

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