αvβ3 Integrin Expression and Mitogenic Effects by Thyroid Hormones in Chronic Lymphocytic Leukemia

Abadi, Uri; Weisz, Avivit; Kidron, Dvora; Katzav, Aviva; Hercbergs, Aleck; Davis, Paul J.; Ellis, Martin; Ashur‐Fabian, Osnat

doi:10.3390/jcm10081766

Cited by 4 publications

(7 citation statements)

References 29 publications

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“…In our previous studies, thyroid hormone binds to the receptor on integrin αvβ3 to activate signal transduction and regulate gene expression of integrin αvβ3 ( Lin et al, 2013 ; Hsieh et al, 2017 ; Abadi et al, 2021 ) and promote cancer cell proliferation ( Lin et al, 2016b ; Ho et al, 2020 ). Our recent findings show that doxycycline affects both gene expression of integrin αv and β3 in MDA-MB-231 cells ( Figure 2B ).…”

Section: Resultsmentioning

confidence: 99%

Role of Integrin αvβ3 in Doxycycline-Induced Anti-Proliferation in Breast Cancer Cells

Chen

Yang

Chu

et al. 2022

Front. Cell Dev. Biol.

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Doxycycline, an antibiotic, displays the inhibition of different signal transduction pathways, such as anti-inflammation and anti-proliferation, in different types of cancers. However, the anti-cancer mechanisms of doxycycline via integrin αvβ3 are incompletely understood. Integrin αvβ3 is a cell-surface anchor protein. It is the target for estrogen, androgen, and thyroid hormone and plays a pivotal role in the proliferation, migration, and angiogenic process in cancer cells. In our previous study, thyroxine hormones can interact with integrin αvβ3 to activate the extracellular signal-regulated kinase 1/2 (ERK1/2), and upregulate programmed death-ligand 1 (PD-L1) expression. In the current study, we investigated the inhibitory effects of doxycycline on proliferation in two breast cancer cell lines, MCF-7 and MDA-MB-231 cells. Doxycycline induces concentration-dependent anti-proliferation in both breast cancer cell lines. It regulates gene expressions involved in proliferation, pro-apoptosis, and angiogenesis. Doxycycline suppresses cell cyclin D1 (CCND1) and c-Myc which play crucial roles in proliferation. It also inhibits PD-L1 gene expression. Our findings show that modulation on integrin αvβ3 binding activities changed both thyroxine- and doxycycline-induced signal transductions by an integrin αvβ3 inhibitor (HSDVHK-NH2). Doxycycline activates phosphorylation of focal adhesion kinase (FAK), a downstream of integrin, but inhibits the ERK1/2 phosphorylation. Regardless, doxycycline-induced FAK phosphorylation is blocked by HSDVHK-NH2. In addition, the specific mechanism of action associated with pERK1/2 inhibition via integrin αvβ3 is unknown for doxycycline treatment. On the other hand, our findings indicated that inhibiting ERK1/2 activation leads to suppression of PD-L1 expression by doxycycline treatment. Furthermore, doxycycline-induced gene expressions are disturbed by a specific integrin αvβ3 inhibitor (HSDVHK-NH2) or a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) kinase (MAPK/ERK, MEK) inhibitor (PD98059). The results imply that doxycycline may interact with integrin αvβ3 and inhibits ERK1/2 activation, thereby regulating cell proliferation and downregulating PD-L1 gene expression in estrogen receptor (ER)-negative breast cancer MDA-MB-231 cells.

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Section: Resultsmentioning

confidence: 99%

Role of Integrin αvβ3 in Doxycycline-Induced Anti-Proliferation in Breast Cancer Cells

Chen

Yang

Chu

et al. 2022

Front. Cell Dev. Biol.

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“…Lamin B1 is presented for the nuclear fraction and actin for the non‐nuclear fractions. Total and membrane fraction were partially presented in our previously published work 23 and are shown with permission. (B) Representative nuclear cell lysates from two CLL patients were denatured and incubated with or without N‐glycosidase (Endo H/PNGase) or O‐glycosidase for 1 h at 37°C, after which WB analysis for the β3 monomer was performed.…”

Section: Resultsmentioning

confidence: 99%

“…The latter was the only disease model in which this modification was also observed in the nucleus, suggesting a differential pattern of post translational modification between different diseases. Based on the fact that 759 tyrosine phosphorylation is specific for outside-in signaling, 23 it is We further demonstrated that PI3K and MAPK, pathways which are closely linked to the integrin signaling in cancer 8,56,57 including leukemia, [58][59][60] regulate nuclear trafficking of the αvβ3 integrin in leukemia. Inhibiting ERK and PI3K in T-ALL and primary CLL cells led to nuclear accumulation of αvβ3 integrin parallel to a reduction in the membrane expression.…”

Section: Post Translational Modification Oncogenic Regulation and Pro...mentioning

confidence: 96%

“…We next used an αvβ3 antibody which recognizes the integrin dimeric epitope, 22 as we reported before in other cancer models. 12,16,17,[23][24][25] Jurkat and HMC-1 cells were stained for αvβ3 (NL557, red) and cell nucleus (Hoechst, blue). To clearly delineate nuclear borders, Lamin B1 staining (NL493, green) was performed.…”

Section: αVβ3 Localizes In the Nucleus Of T-all MCL And Cll Cellsmentioning

confidence: 99%

“…Lamin B1 is presented for the nuclear fraction and actin for the non-nuclear fractions. Total and membrane fraction were partially presented in our previously published work 23 Lastly, we performed immunoprecipitations on nuclear extracts of Jurkat, CLL, and LCL cells using αvβ3 integrin antibody compared to an isotype control. We studied the potential interaction with phosphorylated or non-phosphorylated nuclear ERK, for which we observed a modulating effect on the expression of the nuclear αvβ3.…”

Section: Post Translational Modification Oncogenic Regulation and Pro...mentioning

confidence: 99%

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Nuclear αvβ3 integrin expression, post translational modifications and regulation in hematological malignancies

Weisz

Abadi

Mausbach

et al. 2021

Hematological Oncology

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αvβ3 integrin, a plasma membrane protein, is amply expressed on an array of tumors. We identified nuclear αvβ3 pool in ovarian cancer cells and were interested to explore this phenomenon in two rare and aggressive types of leukemia, T‐cell acute lymphoblastic leukemia (T‐ALL) and Mast cell leukemia (MCL) using Jurkat and HMC‐1 cell lines, respectively. Moreover, we collected primary cells from patients with chronic lymphocytic leukemia (CLL, n = 11), the most common chronic adult leukemia and used human lymphoblastoid cell lines (LCL) generated from normal B cells. Nuclear αvβ3 integrin was assessed by Western blots, confocal microscopy, and the ImageStream technology which combines flow‐cytometry with microscopy. We further examined post translational modifications (phosphorylation/glycosylation), nuclear trafficking regulation using inhibitors for MAPK (U0126) and PI3K (LY294002), as well as nuclear interactions by performing Co‐immunoprecipitation (Co‐IP). αvβ3 integrin was identified in all cell models within the nucleus and is N‐glycosylated. In primary CLL cells the β3 integrin monomer is tyrosine Y759 phosphorylated, suggesting an active receptor conformation. MAPK and PI3K inhibition in Jurkat and CLL cells led to αvβ3 enhancement in the nucleus and a reduction in the membrane. The nuclear αvβ3 integrin interacts with ERK, Histone H3 and Lamin B1 in Jurkat, Histone H3 in CLL cells, but not in control LCL cells. To conclude, this observational study provides the identification of nuclear αvβ3 in hematological malignancies and lays the basis for novel cancer‐relevant actions, which may be independent from the membrane functions.

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Contemporary nano-architectured drugs and leads for ανβ3 integrin-based chemotherapy: Rationale and retrospect

Abbas¹,

Yusuf

Akhtar

et al. 2021

Nanotechnology Reviews

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The integrins belong to the cell-surface polypeptide family and are the mediating partners among the cells, and extracellular matrix (ECM). They are also involved in the biological processes of cell migration, wound healing, blood clotting, immunological response generation, tissue morphogenesis, leucocyte reticulations, and angiogenesis and are therefore very relevant in stem cell technology and are useful as biomarkers, diagnostic probes, and drug-target ligands. The ανβ3 (alpha-nu-beta3) integrin antagonists are an excellent target example for designing and developing newer drug candidates, drug leads and templates for various diseases, and physiological malfunctioning, including cancers. The current review examines the ανβ3 integrin structural features involved in the drug design and its antagonistic ligands and highlights the development of anti-ανβ3 integrin-antagonists as nano-architectural design-based nanomedicine, especially for cancer chemotherapy. The perspectival review discusses the ανβ3 integrin structure, mode of action, involved pathways, and the concepts utilized in nanomedicine design, and ligands related to integrins. It also covers the latest thyrointegrin approaches toward the development of anti-angiogenesis agents and entails the anti-angiogenesis approach to cancer growth inhibition through targeting by the anti-integrin ligands and related chemical entities. The current perspective on the nano-architectural design approach for the known anti-integrin compounds is also outlined.

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αvβ3 Integrin Expression and Mitogenic Effects by Thyroid Hormones in Chronic Lymphocytic Leukemia

Cited by 4 publications

References 29 publications

Role of Integrin αvβ3 in Doxycycline-Induced Anti-Proliferation in Breast Cancer Cells

Role of Integrin αvβ3 in Doxycycline-Induced Anti-Proliferation in Breast Cancer Cells

Nuclear αvβ3 integrin expression, post translational modifications and regulation in hematological malignancies

Contemporary nano-architectured drugs and leads for ανβ3 integrin-based chemotherapy: Rationale and retrospect

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