Endogenous Anti-Cancer Candidates in GPCR, ER Stress, and EMT

Gundamaraju, Rohit; Lu, Wenying; Azimi, Iman; Eri, Rajaraman; Sohal, Sukhwinder Singh

doi:10.3390/biomedicines8100402

Cited by 11 publications

(11 citation statements)

References 76 publications

(101 reference statements)

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“…One study using a pancreatic β-cell line (INS-1 cells) demonstrated that RLX behaves as both an estrogen receptor antagonist through nuclear estrogen response element-dependent actions and as an estrogen receptor agonist by suppressing triglyceride accumulation [ 30 ]. The endoplasmic reticulum (ER) regulates intracellular calcium concentrations and protein folding and trafficking [ 31 , 32 , 33 , 34 ]. ER stress, the disruption of these ER functions, is related to T2DM in humans [ 35 , 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Raloxifene Ameliorates Glucosamine-Induced Insulin Resistance in Ovariectomized Rats

Cheng

Chang

et al. 2021

Biomedicines

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Osteoarthritis (OA) and osteoporosis (OP) are common among older women, especially postmenopausal women. Glucosamine (GlcN) is a common medication for OA, but it may induce insulin resistance and β-cell dysfunction, especially if ovarian hormones are lacking. Raloxifene (RLX) is a selective estrogen receptor modulator and also an OP drug. Previously, we found that estrogen could improve GlcN-induced insulin resistance in ovariectomized (OVX) rats. Here, we further hypothesized that RLX, similarly to estrogen, can ameliorate GlcN-induced insulin resistance in OVX rats. We used GlcN to induce insulin resistance in OVX rats as a model for evaluating the protective effects of RLX in vivo. We used a pancreatic β-cell line, MIN-6, to study the mechanisms underlying the effect of RLX in GlcN-induced β-cell dysfunction in vitro. Increases in fasting plasma glucose, insulin, and homeostasis model assessments of insulin resistance in OVX Sprague Dawley rats treated with GlcN were reversed by RLX treatment (n = 8 in each group). Skeletal muscle GLUT-4 increased, liver PEPCK decreased, pancreatic islet hypertrophy, and β-cell apoptosis in OVX rats treated with GlcN was ameliorated by RLX. The negative effects of GlcN on insulin secretion and cell viability in MIN-6 cells were related to the upregulation of reticulum (ER) stress-associated proteins (C/EBP homologous protein, phospho-extracellular signal-regulated kinase, phospho-c-JunN-terminal kinase), the expression of which was reduced by RLX. Pretreatment with estrogen receptor antagonists reversed the protective effects of RLX. GlcN can induce insulin resistance, β-cell dysfunction, and apoptosis in OVX rats and increase ER stress-related proteins in β-cells, whereas RLX can reverse these adverse effects. The effects of RLX act mainly through estrogen receptor α; therefore, RLX may be a candidate drug for postmenopausal women with OA and OP.

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Section: Introductionmentioning

confidence: 99%

Raloxifene Ameliorates Glucosamine-Induced Insulin Resistance in Ovariectomized Rats

Cheng

Chang

et al. 2021

Biomedicines

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“…Endoplasmic reticulum (ER) stress is responsible for the oncogenic transformation and tumor growth and metastasis 12 , 14 . Coordinating the endoplasmic reticulum stress response is a highly dynamic process that can lead to pro-survival and pro-apoptotic outputs.…”

Section: Discussionmentioning

confidence: 99%

“…ER stress usually occurs after unexpected disturbances such as physiology or pathology 11 . Substantial evidence has clarified that ER stress is involved in multiple types of tumors and plays a pivotal role in mediating tumor survival and death 12 - 14 . Moreover, we previous study had shown that ER stress- mediated cell growth and apoptosis inhibition 9 .…”

Section: Introductionmentioning

confidence: 99%

HRC promotes anoikis resistance and metastasis by suppressing endoplasmic reticulum stress in hepatocellular carcinoma

Xia¹,

Wu²,

Zhou³

et al. 2021

Int. J. Med. Sci.

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Histidine-rich calcium binding protein (HRC) is markedly overexpressed in hepatocellular carcinoma (HCC) and is significantly correlated with metastasis. Anoikis resistance and endoplasmic reticulum (ER) stress may have a critical effect on survival before metastasis. However, the potential functions of HRC in anoikis resistance in HCC remain unknown. Here, we uncovered the clinical value of HRC and its functional significance on anoikis in HCC. The positive expression of HRC was observably correlated with tumor size, tumor encapsulation, and tumor-node-metastasis (TNM) stage. The expression of HRC increased in HCC cells cultured in suspension. HRC enhanced the anoikis resistance of HCC, and promoted the HCC metastasis in vivo. Mechanistically, the anoikis resistance was probably dependent on endoplasmic reticulum stress. Modulating HRC level changed the ERS to affect anoikis resistance by acting protein kinase RNA-like ER kinase (PERK)-eIF2a-ATF4-CHOP signaling axis. In conclusion, we define HRC as a novel candidate oncogene involved in anoikis resistance and HCC metastasis, and provide a new potential therapeutic target for HCC.

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“…GPCRs are the largest family of human cell surface receptors, which has found to contribute to a variety of physiological and pathological processes via transmitting different extracellular signals into cells [29,30]. Recently, several studies revealed that diverse signals activated by GPCR regulated YAP/TAZ activity, positively or negatively, which was dependent on the nature of signals [31][32][33][34][35][36][37].…”

Section: Discussionmentioning

confidence: 99%

TEAD4 Induced Positive Feedback Activation of E2R/YAP1 Axis and Promoted Epithelial-mesenchymal Transition through Up-regulating TWIST1 Directly in HCC

Liu

Shang

et al. 2021

Preprint

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Background: Great advance has been achieved in the investigation of Hippo signaling on mediating carcinogenesis. However, the underlying mechanism that YAP1/TEAD4 signaling regulated hepatocellular carcinoma (HCC) progression have not been completely determined. This investigation aimed to determine the mechanism of activation of YAP1/TEAD4 pathway and its regulatory effect on hepatocarcinogenesis.Methods: The TCGA database and immunohistochemical (IHC) analyses about HCC samples were carried out to analyze the expression of TEAD4 and its correlation with HCC prognosis. CCK-8, wound healing assay and transwell chamber with Matrigel were used to examine the role of TEAD4 on cell proliferation, migration and invasion capacities. In vivo imaging system was used to observe the tumor formation in SCID mouse model. The mechanistic investigation was conducted with functional studies, Western immunoblotting, Luciferase reporter assay, chromatin immunoprecipitation.Results: Analysis of HCC samples revealed that TEAD4 was up-regulated in HCC tissues compared to adjacent liver tissues, and its overexpression in HCC was significantly associated with worse prognosis, high serum AFP level, larger tumor size, PVTT, multiple tumor lesions, and microvascular invasion. Enforced expression of TEAD4 in HCC cell lines promoted the proliferation and growth of HCC cells in vitro and in vivo. The further functional studies showed that TEAD4 increased TWIST1 expression directly in the binding-promoter manner and then enhanced the migration and invasion of HCC cells via inducing epithelial-to-mesenchymal transition (EMT).TWIST1 was found to enhance E2R expression and consequently formed a positive feedback loop to activate the YAP1/TEAD4/TWIST1 axis.Conclusion: This investigation provided the functional and mechanistic basis for identifying the E2R/YAP1/TEAD4/TWIST axis as the oncogenic factor which inducing EMT and then accelerated HCC growth and invasion.

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Endogenous Anti-Cancer Candidates in GPCR, ER Stress, and EMT

Cited by 11 publications

References 76 publications

Raloxifene Ameliorates Glucosamine-Induced Insulin Resistance in Ovariectomized Rats

Raloxifene Ameliorates Glucosamine-Induced Insulin Resistance in Ovariectomized Rats

HRC promotes anoikis resistance and metastasis by suppressing endoplasmic reticulum stress in hepatocellular carcinoma

TEAD4 Induced Positive Feedback Activation of E2R/YAP1 Axis and Promoted Epithelial-mesenchymal Transition through Up-regulating TWIST1 Directly in HCC

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