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Radioresistance of cancer cells, integrin ?v?3 and thyroid hormone.

ABSTRACT: Radioresistance is a substantial barrier to success in cancer management. A number of molecular mechanisms support radioresistance. We have shown experimentally that the thyroid hormone analogue receptor on the extracellular domain of integrin ?v?3 may modulate the state of radiosensitivity of tumor cells. Specifically, tetraiodothyroacetic acid (tetrac), a derivative of L-thyroxine (T4), can reduce radioresistance in cancer cells. In this review, we list a number of intrinsic signal transduction molecules and other host factors that have been reported to support/induce radioresistance in cancer cells and that are also subject to control by T4 through actions primarily initiated at integrin ?v?3. Additional preclinical evidence is needed to support these radioresistance-relevant actions of thyroid hormone.

SUBMITTER: Leith JT

PROVIDER: S-EPMC6319341 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Radioresistance of cancer cells, integrin αvβ3 and thyroid hormone.

Leith John T JT Mousa Shaker A SA Hercbergs Aleck A Lin Hung-Yun HY Davis Paul J PJ

Oncotarget 20181211 97

Radioresistance is a substantial barrier to success in cancer management. A number of molecular mechanisms support radioresistance. We have shown experimentally that the thyroid hormone analogue receptor on the extracellular domain of integrin αvβ3 may modulate the state of radiosensitivity of tumor cells. Specifically, tetraiodothyroacetic acid (tetrac), a derivative of L-thyroxine (T<sub>4</sub>), can reduce radioresistance in cancer cells. In this review, we list a number of intrinsic signal ...[more]

PMID: 30651936

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Crosstalk between integrin αvβ3 and ERα contributes to thyroid hormone-induced proliferation of ovarian cancer cells.

Project description:Ovarian cancer is the leading cause of death in gynecological diseases. Thyroid hormone promotes proliferation of ovarian cancer cells via cell surface receptor integrin αvβ3 that activates extracellular regulated kinase (ERK1/2). However, the mechanisms are still not fully understood. Thyroxine (T4) at a physiologic total hormone concentration (10-7 M) significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3'-triiodo-L-thyronine (T3) at a supraphysiologic concentration. Thyroid hormone (T4 and T3) treatment of human ovarian cancer cells resulted in enhanced activation of the Ras/MAPK(ERK1/2) signal transduction pathway. An MEK inhibitor (PD98059) blocked hormone-induced cell proliferation but not ER phosphorylation. Knock-down of either integrin αv or β3 by RNAi blocked thyroid hormone-induced phosphorylation of ERK1/2. We also found that thyroid hormone causes elevated phosphorylation and nuclear enrichment of estrogen receptor α (ERα). Confocal microscopy indicated that both T4 and estradiol (E2) caused nuclear translocation of integrin αv and phosphorylation of ERα. The specific ERα antagonist (ICI 182,780; fulvestrant) blocked T4-induced ERK1/2 activation, ERα phosphorylation, PCNA expression and proliferation. The nuclear co-localization of integrin αv and phosphorylated ERα was inhibited by ICI. ICI time-course studies indicated that mechanisms involved in T4- and E2-induced nuclear co-localization of phosphorylated ERα and integrin αv are dissimilar. Chromatin immunoprecipitation results showed that T4-induced binding of integrin αv monomer to ERα promoter and this was reduced by ICI. In summary, thyroid hormone stimulates proliferation of ovarian cancer cells via crosstalk between integrin αv and ERα, mimicking functions of E2.

| S-EPMC5421843 | biostudies-literature

?v?3 Integrin Mediates Radioresistance of Prostate Cancer Cells through Regulation of Survivin.

Project description:The ?v?3 integrin is involved in various physiologic and pathologic processes such as wound healing, angiogenesis, tumor growth, and metastasis. The impact of ?v?3 integrin on the radiosensitivity of prostate cancer cells and the molecular mechanism controlling cell survival in response to ionizing radiation (IR) was investigated. Both LNCaP cells stably transfected with ?v?3 integrin and PC-3 cells that contain endogenous ?3 integrin were used. This study demonstrated that ?v?3 integrin increases survival of ?v?3-LNCaP cells upon IR while small hairpin RNA (shRNA)-mediated knockdown of ?v?3 integrin in PC-3 cells sensitizes to radiation. Expression of ?v?3 integrin in LNCaP cells also enhances anchorage-independent cell growth while knockdown of ?v?3 integrin in PC-3 cells inhibits anchorage-independent cell growth. The ?v?3 antagonist, cRGD, significantly increases radiosensitivity in both ?v?3-LNCaP and PC-3 cells. Moreover, ?v?3 integrin prevents radiation-induced downregulation of survivin. Inhibition of survivin expression by siRNA or shRNA enhances IR-induced inhibition of anchorage-independent cell growth. Overexpression of wild-type survivin in PC-3 cells treated with ?v?3 integrin shRNA increases survival of cells upon IR. These findings reveal that ?v?3 integrin promotes radioresistance and regulates survivin levels in response to IR. IMPLICATIONS: Future translational research on targeting ?v?3 integrin and survivin may reveal novel approaches as an adjunct to radiotherapy for patients with prostate cancer.

| S-EPMC6359981 | biostudies-literature

Thyroid hormone differentially modulates Warburg phenotype in breast cancer cells.

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| S-EPMC3207240 | biostudies-literature

NF-κB regulates radioresistance mediated by β1-integrin in three-dimensional culture of breast cancer cells.

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| S-EPMC3698967 | biostudies-literature

Thyroid hormone regulates adhesion, migration and matrix metalloproteinase 9 activity via ?v?3 integrin in myeloma cells.

Project description:Thyroid hormone (3,5,3'-triiodothyronine, T3; L-thyroxine, T4) enhances cancer cell proliferation, invasion and angiogenesis via a discrete receptor located near the RGD recognition site on ?v?3 integrin. Tetraiodothyroacetic acid (tetrac) and its nanoparticulate formulation interfere with binding of T3/T4 to the integrin. This integrin is overexpressed in multiple myeloma (MM) and other cancers. MM cells interact with ?v?3 integrin to support growth and invasion. Matrix metalloproteinases (MMPs) are a family of enzymes active in tissue remodeling and cancer. The association between integrins and MMPs secretion and action is well established. In the current study, we examined the effects of thyroid hormone on myeloma cell adhesion, migration and MMP activity. We show that T3 and T4 increased myeloma adhesion to fibronectin and induced ?v?3 clustering. In addition, the hormones induced MMP-9 expression and activation via ?v?3 and MAPK induction. Bortezomib, a standard myeloma treatment, caused a decrease in activity/quantity of MMPs and thyroid hormone opposed this effect. RGD peptide and tetrac impaired the production of MMP-9 in cell lines and in primary BM cells from myeloma patients. In conclusion, thyroid hormone-dependent regulation via ?v?3 of myeloma cell adhesion and MMP-9 production may play a role in myeloma migration and progression.

| S-EPMC4171632 | biostudies-literature

Thyroid dysfunction, thyroid hormone replacement and colorectal cancer risk.

Project description:BackgroundCurrent screening guidelines for colorectal cancer (CRC) do not consider thyroid dysfunction as a risk factor for disease development. We sought to determine the risk of developing CRC in patients with thyroid dysfunction, with and without thyroid hormone replacement (THR).MethodsWe conducted a nested case-control study using a large population-based medical records database from the United Kingdom. Study case patients were defined as those with any medical code of CRC. Subjects with familial colorectal cancer syndromes or inflammatory bowel disease (IBD) were excluded. For every case patient, four eligible control patients matched on age, sex, practice site, and duration of follow-up before index date were selected using incidence density sampling. Exposure was THR therapy before index date. We further divided the THR unexposed group into patients with hypothyroidism (TSH > 4 mg/dl), patients with hyperthyroidism (TSH < 0.4 mg/dl), and subjects without documented thyroid abnormality. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for CRC were estimated using conditional logistic regression. All statistical tests were two-sided.ResultsWe identified 20990 CRC patients and 82054 control patients. The adjusted odds ratio for CRC associated with THR was 0.88 (95% CI = 0.79 to 0.99, P = .03) and 0.68 (95% CI = 0.55 to 0.83, P < .001) for treatment initiated five to 10 years and more than 10 years before index date, respectively. This protective association increased with cumulative duration of therapy. In contrast, hyperthyroidism (adjusted OR = 1.21, 95% CI = 1.08 to 1.36, P = .001) or untreated hypothyroidism (adjusted OR = 1.16, 95% CI = 1.08 to 1.24, P < .001) were associated with increased risk of CRC.ConclusionLong-term THR is associated with a decreased risk of CRC. Hyperthyroidism and untreated hypothyroidism are associated with modestly elevated risk of CRC.

| S-EPMC4838062 | biostudies-literature

Thyroid Hormone Receptor ? Inhibits Self-Renewal Capacity of Breast Cancer Stem Cells.

Project description:Background: A subpopulation of cancer stem cells (CSCs) with capacity for self-renewal is believed to drive initiation, progression, and relapse of breast tumors. Methods: Since the thyroid hormone receptor ? (TR?) appears to suppress breast tumor growth and metastasis, we have analyzed the possibility that TR? could affect the CSC population using MCF-7 cells grown under adherent conditions or as mammospheres, as well as inoculation into immunodeficient mice. Results: Treatment of TR?-expressing MCF-7 cells (MCF7-TR? cells) with the thyroid hormone triiodothyronine (T3) decreased significantly CD44+/CD24- and ALDH+ cell subpopulations, the efficiency of mammosphere formation, the self-renewal capacity of CSCs in limiting dilution assays, the expression of the pluripotency factors in the mammospheres, and tumor initiating capacity in immunodeficient mice, indicating that the hormone reduces the CSC population present within the bulk MCF7-TR? cultures. T3 also decreased migration and invasion, a hallmark of CSCs. Transcriptome analysis showed downregulation of the estrogen receptor alpha (ER?) and ER-responsive genes by T3. Furthermore, among the T3-repressed genes, there was an enrichment in genes containing binding sites for transcription factors that are key determinants of luminal-type breast cancers and are required for ER binding to chromatin. Conclusion: We demonstrate a novel role of TR? in the biology of CSCs that may be related to its action as a tumor suppressor in breast cancer.

| S-EPMC6998057 | biostudies-literature

Thyroid Hormone Receptor-? (TR?) Mediates Runt-Related Transcription Factor 2 (Runx2) Expression in Thyroid Cancer Cells: A Novel Signaling Pathway in Thyroid Cancer.

Project description:Dysregulation of the thyroid hormone receptor (TR)? is common in human cancers. Restoration of functional TR? delays tumor progression in models of thyroid and breast cancers implicating TR? as a tumor suppressor. Conversely, aberrant expression of the runt-related transcription factor 2 (Runx2) is established in the progression and metastasis of thyroid, breast, and other cancers. Silencing of Runx2 diminishes tumor invasive characteristics. With TR? as a tumor suppressor and Runx2 as a tumor promoter, a compelling question is whether there is a functional relationship between these regulatory factors in thyroid tumorigenesis. Here, we demonstrated that these proteins are reciprocally expressed in normal and malignant thyroid cells; TR? is high in normal cells, and Runx2 is high in malignant cells. T3 induced a time- and concentration-dependent decrease in Runx2 expression. Silencing of TR? by small interfering RNA knockdown resulted in a corresponding increase in Runx2 and Runx2-regulated genes, indicating that TR? levels directly impact Runx2 expression and associated epithelial to mesenchymal transition molecules. TR? specifically bound to 3 putative thyroid hormone-response element motifs within the Runx2-P1 promoter ((-)105/(+)133) as detected by EMSA and chromatin immunoprecipitation. TR? suppressed Runx2 transcriptional activities, thus confirming TR? regulation of Runx2 at functional thyroid hormone-response elements. Significantly, these findings indicate that a ratio of the tumor-suppressor TR? and tumor-promoting Runx2 may reflect tumor aggression and serve as biomarkers in biopsy tissues. The discovery of this TR?-Runx2 signaling supports the emerging role of TR? as a tumor suppressor and reveals a novel pathway for intervention.

| S-EPMC4967127 | biostudies-literature

Thyroid hormone-dependent oligodendroglial cell lineage genomic and non-genomic signaling through integrin receptors.

Project description:Multiple sclerosis (MS) is a heterogeneous autoimmune disease whereby the pathological sequelae evolve from oligodendrocytes (OLs) within the central nervous system and are targeted by the immune system, which causes widespread white matter pathology and results in neuronal dysfunction and neurological impairment. The progression of this disease is facilitated by a failure in remyelination following chronic demyelination. One mediator of remyelination is thyroid hormone (TH), whose reliance on monocarboxylate transporter 8 (MCT8) was recently defined. MCT8 facilitates the entry of THs into oligodendrocyte progenitor cell (OPC) and pre-myelinating oligodendrocytes (pre-OLs). Patients with MS may exhibit downregulated MCT8 near inflammatory lesions, which emphasizes an inhibition of TH signaling and subsequent downstream targeted pathways such as phosphoinositide 3-kinase (PI3K)-Akt. However, the role of the closely related mammalian target of rapamycin (mTOR) in pre-OLs during neuroinflammation may also be central to the remyelination process and is governed by various growth promoting signals. Recent research indicates that this may be reliant on TH-dependent signaling through β1-integrins. This review identifies genomic and non-genomic signaling that is regulated through mTOR in TH-responsive pre-OLs and mature OLs in mouse models of MS. This review critiques data that implicates non-genomic Akt and mTOR signaling in response to TH-dependent integrin receptor activation in pre-OLs. We have also examined whether this can drive remyelination in the context of neuroinflammation and associated sequelae. Importantly, we outline how novel therapeutic small molecules are being designed to target integrin receptors on oligodendroglial lineage cells and whether these are viable therapeutic options for future use in clinical trials for MS.

| S-EPMC9483185 | biostudies-literature

Thyroid hormone receptor mutations in cancer and resistance to thyroid hormone: perspective and prognosis.

Project description:Thyroid hormone, operating through its receptors, plays crucial roles in the control of normal human physiology and development; deviations from the norm can give rise to disease. Clinical endocrinologists often must confront and correct the consequences of inappropriately high or low thyroid hormone synthesis. Although more rare, disruptions in thyroid hormone endocrinology due to aberrations in the receptor also have severe medical consequences. This review will focus on the afflictions that are caused by, or are closely associated with, mutated thyroid hormone receptors. These include Resistance to Thyroid Hormone Syndrome, erythroleukemia, hepatocellular carcinoma, renal clear cell carcinoma, and thyroid cancer. We will describe current views on the molecular bases of these diseases, and what distinguishes the neoplastic from the non-neoplastic. We will also touch on studies that implicate alterations in receptor expression, and thyroid hormone levels, in certain oncogenic processes.

| S-EPMC3134260 | biostudies-other

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