scholarly journals TYRO3: A potential therapeutic target in cancer

2019 ◽  
Vol 244 (2) ◽  
pp. 83-99 ◽  
Author(s):  
Pei-Ling Hsu ◽  
Jonathan Jou ◽  
Shaw-Jenq Tsai
Keyword(s):  
Molecular Biology ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Epithelial Mesenchymal Transition ◽  
Protein S ◽  
Targeted Treatment ◽  
Novel Therapy ◽  
Mesenchymal Transition ◽  
Promote Cell Proliferation

TYRO3 belongs to the TAM (TYRO3, AXL, and MER) receptor family, a unique subfamily of the receptor tyrosine kinases. Members of TAM family share the same ligand, growth arrest-specific 6, and protein S. Although the signal transduction pathways of TYRO3 have not been evaluated in detail, overexpression and activation of TYRO3 receptor tyrosine kinase have been reported to promote cell proliferation, survival, tumorigenesis, migration, invasion, epithelial-mesenchymal transition, or chemoresistance in several human cancers. Targeting TYRO3 could break the kinase signaling, stimulate antitumor immunity, reduce tumor cell survival, and regain drug sensitivity. To date, there is no specific TYRO3-targeted drug, the effectiveness of targeting TYRO3 in cancer is worthy of further investigations. In this review, we present an update on molecular biology of TYRO3, summarize the development of potential inhibitors of TAM family members, and provide new insights in TYRO3-targeted treatment. Impact statement Cancer is among the leading causes of death worldwide. In 2016, 8.9 million people are estimated to have died from various forms of cancer. The current treatments, including surgery with chemotherapy and/or radiation therapy, are not effective enough to provide full protection from cancer, which highlights the need for developing novel therapy strategies. In this review, we summarize the molecular biology of a unique member of a subfamily of receptor tyrosine kinase, TYRO3 and discuss the new insights in TYRO3-targeted treatment for cancer therapy.

scholarly journals The Role of the Receptor Tyrosine Kinase Axl in Carcinogenesis and Development of Therapeutic Resistance: An Overview of Molecular Mechanisms and Future Applications

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1521
Author(s):  
Martha Wium ◽  
Aderonke F. Ajayi-Smith ◽  
Juliano D. Paccez ◽  
Luiz F. Zerbini
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Cancer Progression ◽  
Receptor Tyrosine Kinase ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Chemotherapeutic Agents ◽  
Mesenchymal Transition ◽  
Development Of Resistance

Resistance to chemotherapeutic agents by cancer cells has remained a major obstacle in the successful treatment of various cancers. Numerous factors such as DNA damage repair, cell death inhibition, epithelial–mesenchymal transition, and evasion of apoptosis have all been implicated in the promotion of chemoresistance. The receptor tyrosine kinase Axl, a member of the TAM family (which includes TYRO3 and MER), plays an important role in the regulation of cellular processes such as proliferation, motility, survival, and immunologic response. The overexpression of Axl is reported in several solid and hematological malignancies, including non-small cell lung, prostate, breast, liver and gastric cancers, and acute myeloid leukaemia. The overexpression of Axl is associated with poor prognosis and the development of resistance to therapy. Reports show that Axl overexpression confers drug resistance in lung cancer and advances the emergence of tolerant cells. Axl is, therefore, an important candidate as a prognostic biomarker and target for anticancer therapies. In this review, we discuss the consequence of Axl upregulation in cancers, provide evidence for its role in cancer progression and the development of drug resistance. We will also discuss the therapeutic potential of Axl in the treatment of cancer.

scholarly journals Ectopic repression of receptor tyrosine kinase–like orphan receptor 2 inhibits malignant transformation of ovarian cancer cells by reversing epithelial–mesenchymal transition

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831770162 ◽  
Author(s):  
Ying Xu ◽  
Yan-Hui Ma ◽  
Ying-Xin Pang ◽  
Zhe Zhao ◽  
Jing-Jing Lu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Epithelial Mesenchymal Transition ◽  
Orphan Receptor ◽  
Ovarian Cancer Cells ◽  
Mesenchymal Transition ◽  
Tumor Tissues ◽  
Canonical Wnt

Receptor tyrosine kinase–like orphan receptor 2 is an enzyme-linked receptor which specifically modulates WNT5A signaling and plays an important role in tumorigenesis, invasion, and metastasis; however, the precise role of receptor tyrosine kinase–like orphan receptor 2 in cancer is controversial. The purpose of this study was to investigate the expression and role of receptor tyrosine kinase–like orphan receptor 2 in ovarian carcinoma and clarify the biological functions and interactions of receptor tyrosine kinase–like orphan receptor 2 with non-canonical Wnt pathways in ovarian cancer. The result of the human ovary tissue microarray revealed that the receptor tyrosine kinase–like orphan receptor 2–positive rate increased in malignant epithelial ovarian cancers and was extremely higher in the metastatic tumor tissues, which was also higher than that in the malignant ovarian tumor tissues. In addition, high expression of receptor tyrosine kinase–like orphan receptor 2 was closely related with ovarian cancer grading. The expression of receptor tyrosine kinase–like orphan receptor 2 protein was higher in SKOV3 and A2780 cells than OVCAR3 and 3AO cells. Knockdown of receptor tyrosine kinase–like orphan receptor 2 inhibited ovarian cancer cell proliferation, migration, invasion, and induced morphologic as well as digestive state alterations in stably transfected SKOV3 cells. Detailed study further revealed that silencing of receptor tyrosine kinase–like orphan receptor 2 reversed the epithelial–mesenchymal transition and inhibited non-canonical Wnt signaling. Our findings suggest that receptor tyrosine kinase–like orphan receptor 2 may be an important regulator of epithelial–mesenchymal transition, primarily regulated the non-canonical Wnt signaling pathway in ovarian cancer cells, and may display a promising therapeutic target for ovarian cancer.

scholarly journals Chromatin-directed proteomics-identified network of endogenous androgen receptor in prostate cancer cells

Oncogene ◽  
2021 ◽  
Author(s):  
Kaisa-Mari Launonen ◽  
Ville Paakinaho ◽  
Gianluca Sigismondo ◽  
Marjo Malinen ◽  
Reijo Sironen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Protein A ◽  
Chorioallantoic Membrane ◽  
Chromatin Accessibility ◽  
Castration Resistant Prostate Cancer ◽  
Novel Therapy ◽  
Mesenchymal Transition

AbstractTreatment of prostate cancer confronts resistance to androgen receptor (AR)-targeted therapies. AR-associated coregulators and chromatin proteins hold a great potential for novel therapy targets. Here, we employed a powerful chromatin-directed proteomics approach termed ChIP-SICAP to uncover the composition of chromatin protein network, the chromatome, around endogenous AR in castration resistant prostate cancer (CRPC) cells. In addition to several expected AR coregulators, the chromatome contained many nuclear proteins not previously associated with the AR. In the context of androgen signaling in CRPC cells, we further investigated the role of a known AR-associated protein, a chromatin remodeler SMARCA4 and that of SIM2, a transcription factor without a previous association with AR. To understand their role in chromatin accessibility and AR target gene expression, we integrated data from ChIP-seq, RNA-seq, ATAC-seq and functional experiments. Despite the wide co-occurrence of SMARCA4 and AR on chromatin, depletion of SMARCA4 influenced chromatin accessibility and expression of a restricted set of AR target genes, especially those involved in cell morphogenetic changes in epithelial-mesenchymal transition. The depletion also inhibited the CRPC cell growth, validating SMARCA4’s functional role in CRPC cells. Although silencing of SIM2 reduced chromatin accessibility similarly, it affected the expression of a much larger group of androgen-regulated genes, including those involved in cellular responses to external stimuli and steroid hormone stimulus. The silencing also reduced proliferation of CRPC cells and tumor size in chick embryo chorioallantoic membrane assay, further emphasizing the importance of SIM2 in CRPC cells and pointing to the functional relevance of this potential prostate cancer biomarker in CRPC cells. Overall, the chromatome of AR identified in this work is an important resource for the field focusing on this important drug target.

scholarly journals Role of the ABL tyrosine kinases in the epithelial–mesenchymal transition and the metastatic cascade

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jillian Hattaway Luttman ◽  
Ashley Colemon ◽  
Benjamin Mayro ◽  
Ann Marie Pendergast
Keyword(s):  
Solid Tumors ◽  
Tyrosine Kinases ◽  
Epithelial To Mesenchymal Transition ◽  
Kinase Inhibitors ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Effects ◽  
Mesenchymal Transition ◽  
Metastatic Cascade ◽  
Abl Kinases ◽  
Treatment Paradigm

AbstractThe ABL kinases, ABL1 and ABL2, promote tumor progression and metastasis in various solid tumors. Recent reports have shown that ABL kinases have increased expression and/or activity in solid tumors and that ABL inactivation impairs metastasis. The therapeutic effects of ABL inactivation are due in part to ABL-dependent regulation of diverse cellular processes related to the epithelial to mesenchymal transition and subsequent steps in the metastatic cascade. ABL kinases target multiple signaling pathways required for promoting one or more steps in the metastatic cascade. These findings highlight the potential utility of specific ABL kinase inhibitors as a novel treatment paradigm for patients with advanced metastatic disease.

scholarly journals Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

2021 ◽  
Vol 14 (7) ◽  
pp. 626
Author(s):  
Julie Bolcaen ◽  
Shankari Nair ◽  
Cathryn H. S. Driver ◽  
Tebatso M. G. Boshomane ◽  
Thomas Ebenhan ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Radionuclide Therapy ◽  
Kinase Inhibitors ◽  
Nuclear Imaging ◽  
Therapy Resistance ◽  
Targeted Radionuclide Therapy ◽  
Therapy Strategy ◽  
Dismal Prognosis

Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact on tumor progression and therapy resistance. Therefore, receptor tyrosine kinase inhibitors (RTKIs) have been investigated to improve the dismal prognosis of GB in an effort to evolve into a personalized targeted therapy strategy with a better treatment outcome. Numerous RTKIs have been approved in the clinic and several radiopharmaceuticals are part of (pre)clinical trials as a non-invasive method to identify patients who could benefit from RTKI. The latter opens up the scope for theranostic applications. In this review, the present status of RTKIs for the treatment, nuclear imaging and targeted radionuclide therapy of GB is presented. The focus will be on seven tyrosine kinase receptors, based on their central role in GB: EGFR, VEGFR, MET, PDGFR, FGFR, Eph receptor and IGF1R. Finally, by way of analyzing structural and physiological characteristics of the TKIs with promising clinical trial results, four small molecule RTKIs were selected based on their potential to become new therapeutic GB radiopharmaceuticals.

Signaling in new directions

1995 ◽  
Vol 73 (3-4) ◽  
pp. 133-136 ◽  
Author(s):  
Haleh Vahidi Samiei
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Map Kinase ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Molecular Level ◽  
Clear Cut ◽  
New Directions

Many laboratories, using a variety of organisms, have contributed to deciphering the identity and the order of the components leading from ligand-bound receptor tyrosine kinases to various intracellular events, including changes in gene expression. The gaps have only been filled recently. This minireview summarizes the findings and points out the degree of conservation of the same pathway in distant organisms, both at the molecular level and in terms of the consecutive steps. The review also looks at points at which this pathway might be diverging and points onto which other pathways might be converging. These interactions are not always clear cut, and understanding them will be the challenge for the future.Key words: signal transduction, receptor tyrosine kinase, RAS, RAF, MAP kinase.

scholarly journals Helicobacter Pylori Targets the EPHA2 Receptor Tyrosine Kinase in Gastric Cells Modulating Key Cellular Functions

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 513 ◽  
Author(s):  
Marina Leite ◽  
Miguel S. Marques ◽  
Joana Melo ◽  
Marta T. Pinto ◽  
Bruno Cavadas ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Receptor Activation ◽  
Degradation Pathway ◽  
Mrna Levels ◽  
H Pylori

Helicobacter pylori, a stomach-colonizing Gram-negative bacterium, is the main etiological factor of various gastroduodenal diseases, including gastric adenocarcinoma. By establishing a life-long infection of the gastric mucosa, H. pylori continuously activates host-signaling pathways, in particular those associated with receptor tyrosine kinases. Using two different gastric epithelial cell lines, we show that H. pylori targets the receptor tyrosine kinase EPHA2. For long periods of time post-infection, H. pylori induces EPHA2 protein downregulation without affecting its mRNA levels, an effect preceded by receptor activation via phosphorylation. EPHA2 receptor downregulation occurs via the lysosomal degradation pathway and is independent of the H. pylori virulence factors CagA, VacA, and T4SS. Using small interfering RNA, we show that EPHA2 knockdown affects cell–cell and cell–matrix adhesion, invasion, and angiogenesis, which are critical cellular processes in early gastric lesions and carcinogenesis mediated by the bacteria. This work contributes to the unraveling of the underlying mechanisms of H. pylori–host interactions and associated diseases. Additionally, it raises awareness for potential interference between H. pylori infection and the efficacy of gastric cancer therapies targeting receptors tyrosine kinases, given that infection affects the steady-state levels and dynamics of some receptor tyrosine kinases (RTKs) and their signaling pathways.

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