TMCO1 mediates cancer cell migration through regulating microtubule assembling

Transmembrane and coiled-coil domains 1 (TMCO1) is highly conserved in amino acid sequence among species and ubiquitously expressed in all human tissues. Homozygous frameshift mutation in TMCO1 causes distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. However, its physiological functions, particularly in cancer biology, are largely unknown. In this study, we have found that knock down of TMCO1 in HeLa cells, a human cervical cancer cell line, and U2OS cells, an osteosarcoma cell line, remarkably inhibited their migratory capability; TMCO1 was highly expressed in the cells of the invasive front of high grade lung cancer and metastatic cancer cells in the clinical specimens, and lung cancer cells at the metastatic bone site in our animal model; Immunohistostaining revealed that TMCO1 was co-localized with microtubules and was able to be co-sedimentated with microtubules in the presence of paclitaxel and GTP; and deficiency of TMCO1 in cells dramatically increased acetylation of tubulin. Further investigation demonstrated that TMCO1 impacted microtubule dynamics, which is closely correlated with cancer metastasis, TBA drug response and therapeutic prognosis. Our findings provide not only new mechanistic insights into cancer metastasis, but also critically evaluate the significance of TMCO1 as a novel target for therapeutic treatment of the disease.https://engagedscholarship.csuohio.edu/u_poster_2015/1016/thumbnail.jp

TMCO1 is a novel target for cancer chemotherapy

Transmembrane and coiled-coil domains 1 (TMCO1) is a protein of 22 KDa highly conserved in amino acid sequence among mammalian species and functions as an endoplasmic reticulum (ER) Ca2+load-activated Ca2+channel. Homozygous frameshift mutation in TMCO1 causes distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. However, its physiological functions are largely unknown. In this study, we found that TMCO1 was co-localized with microtubules as determined by immunohistostaining and a co-sedimentation assay. Interestingly, TMCO1 was highly expressed in the invasive front of high grade lung cancer and metastatic cancer cells of clinical specimens. To further investigate the biological role of TMCO1 in lung cancer, we knocked it down in A549 cells, a human lung adenocarcinoma cell line, by using shRNA lentiviral particles. Disruption of TMCO1 in the cells resulted in delayed microtubule polymerization and remarkably increased acetylation of -tubulin. In addition, A549 cells lacking of TMCO1 grew significantly slower than the control cells. Taken together, our findings suggest that TMCO1 may be a therapeutic target for lung cancer treatment.https://engagedscholarship.csuohio.edu/u_poster_2018/1031/thumbnail.jp

RNase L contributes to lipid metabolism

Macrophage-derived foam cell formation is a milestone of the atherosclerotic lesion initiation and progression, leading to cardiovascular diseases and stroke. Foam cells are formed from the disruption of a homeostatic mechanism that manipulates the uptake, intracellular metabolism and efflux of cholesterol within macrophages. Although studies have yielded much information about the homeostatic mechanism, the molecular basis of foam cell formation remains to be fully understood. We recently found that deficiency of RNase L attenuated macrophage functions including macrophage migration and its endocytic activity. Furthermore, RNase L markedly impacted the expression of certain pro- and anti-foam cell genes in macrophages. Most interestingly we have revealed that lack of RNase L significantly increased the formation of foam cells from bone marrow derived macrophages (BMMs). The increase of foam cell formation was associated with up-regulation of the expression of scavenger receptors such as CD36, SR-A, and PPAR-g. These studies provide new insights into foam cell formation and novel therapeutic strategies for atherosclerosis may be designed through activation/up-regulation of RNase L.https://engagedscholarship.csuohio.edu/u_poster_2014/1001/thumbnail.jp

Copalic Acid Analogs Down-regulate Androgen Receptor and Inhibit Small Chaperone Protein

Copalic acid, one of the diterpenoid acids in copaiba oil, inhibited the chaperone function of α-crystallin and heat shock protein 27 kD (HSP27). It also showed potent activity in decreasing an HSP27 client protein, androgen receptor (AR), which makes it useful in prostate cancer treatment or prevention. To develop potent drug candidates to decrease the AR level in prostate cancer cells, more copalic acid analogs were synthesized. Using the level of AR as the readout, 15 of the copalic acid analogs were screened and two compounds were much more potent than copalic acid. The compounds also dose-dependently inhibited AR positive prostate cancer cell growth. Furthermore, they inhibited the chaperone activity of α-crystallin as well

Copalic Acid Analogs Down-regulate Androgen Receptor and Inhibit Small Chaperone Protein

Copalic acid, one of the diterpenoid acids in copaiba oil, inhibited the chaperone function of α-crystallin and heat shock protein 27 kD (HSP27). It also showed potent activity in decreasing an HSP27 client protein, androgen receptor (AR), which makes it useful in prostate cancer treatment or prevention. To develop potent drug candidates to decrease the AR level in prostate cancer cells, more copalic acid analogs were synthesized. Using the level of AR as the readout, 15 of the copalic acid analogs were screened and two compounds were much more potent than copalic acid. The compounds also dose-dependently inhibited AR positive prostate cancer cell growth. Furthermore, they inhibited the chaperone activity of α-crystallin as well

Role and therapeutic potential of DEAD-box RNA helicase family in colorectal cancer

Colorectal cancer (CRC) is the third most commonly diagnosed and the second cancer-related death worldwide, leading to more than 0.9 million deaths every year. Unfortunately, this disease is changing rapidly to a younger age, and in a more advanced stage when diagnosed. The DEAD-box RNA helicase proteins are the largest family of RNA helicases so far. They regulate almost every aspect of RNA physiological processes, including RNA transcription, editing, splicing and transport. Aberrant expression and critical roles of the DEAD-box RNA helicase proteins have been found in CRC. In this review, we first summarize the protein structure, cellular distribution, and diverse biological functions of DEAD-box RNA helicases. Then, we discuss the distinct roles of DEAD-box RNA helicase family in CRC and describe the cellular mechanism of actions based on recent studies, with an aim to provide future strategies for the treatment of CRC

RNase L Contributes to Experimentally Induced Type 1 Diabetes Onset in Mice

The cause of type 1 diabetes continues to be a focus of investigation. Studies have revealed that interferon α (IFNα) in pancreatic islets after viral infection or treatment with double-stranded RNA (dsRNA), a mimic of viral infection, is associated with the onset of type 1 diabetes. However, how IFNα contributes to the onset of type 1 diabetes is obscure. In this study, we found that 2-5A-dependent RNase L (RNase L), an IFNα-inducible enzyme that functions in the antiviral and antiproliferative activities of IFN, played an important role in dsRNA-induced onset of type 1 diabetes. Using RNase L-deficient, rat insulin promoter-B7.1 transgenic mice, which are more vulnerable to harmful environmental factors such as viral infection, we demonstrated that deficiency of RNase L in mice resulted in a significant delay of diabetes onset induced by polyinosinic:polycytidylic acid (poly I:C), a type of synthetic dsRNA, and streptozotocin, a drug which can artificially induce type 1-like diabetes in experimental animals. Immunohistochemical staining results indicated that the population of infiltrated CD8+T cells was remarkably reduced in the islets of RNase L-deficient mice, indicating that RNase L may contribute to type 1 diabetes onset through regulating immune responses. Furthermore, RNase L was responsible for the expression of certain proinflammatory genes in the pancreas under induced conditions. Our findings provide new insights into the molecular mechanism underlying β-cell destruction and may indicate novel therapeutic strategies for treatment and prevention of the disease based on the selective regulation and inhibition of RNase L

RNase L Contributes to Experimentally Induced Type 1 Diabetes Onset in Mice

The cause of type 1 diabetes continues to be a focus of investigation. Studies have revealed that interferon α (IFNα) in pancreatic islets after viral infection or treatment with double-stranded RNA (dsRNA), a mimic of viral infection, is associated with the onset of type 1 diabetes. However, how IFNα contributes to the onset of type 1 diabetes is obscure. In this study, we found that 2-5A-dependent RNase L (RNase L), an IFNα-inducible enzyme that functions in the antiviral and antiproliferative activities of IFN, played an important role in dsRNA-induced onset of type 1 diabetes. Using RNase L-deficient, rat insulin promoter-B7.1 transgenic mice, which are more vulnerable to harmful environmental factors such as viral infection, we demonstrated that deficiency of RNase L in mice resulted in a significant delay of diabetes onset induced by polyinosinic:polycytidylic acid (poly I:C), a type of synthetic dsRNA, and streptozotocin, a drug which can artificially induce type 1-like diabetes in experimental animals. Immunohistochemical staining results indicated that the population of infiltrated CD8+T cells was remarkably reduced in the islets of RNase L-deficient mice, indicating that RNase L may contribute to type 1 diabetes onset through regulating immune responses. Furthermore, RNase L was responsible for the expression of certain proinflammatory genes in the pancreas under induced conditions. Our findings provide new insights into the molecular mechanism underlying β-cell destruction and may indicate novel therapeutic strategies for treatment and prevention of the disease based on the selective regulation and inhibition of RNase L

Vascular endothelial growth factor and the risk of venous thromboembolism: A genetic correlation and two-sample Mendelian randomization study

Background: The relationship between vascular endothelial growth factor (VEGF) and the risk of venous thromboembolism (VTE) has always been one of the concerns in the medical field. However, the causal inferences from published observational studies on this issue may be affected by confounders or reverse causality. We performed a two-sample bidirectional Mendelian randomization (MR) to infer the associations between VEGF and VTE. Methods: Summary statistics from genome-wide association studies (GWAS) for VEGF and VTE were obtained from published meta-analysis studies and the FinnGen consortium, respectively. Independent genetic variables significantly associated with exposure were selected as instrumental variables. Linkage disequilibrium score regression (LDSC) and five robust MR analytical approaches were conducted to estimate the genetic correlations and causal inference. The MR-Egger intercept, Cochran’s Q, and MR pleiotropy residual sum and outlier (MR-PRESSO) were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on outcomes. Notably, replication analyses were performed using different subgroups of VTE. Results: LDSC failed to identify genetic correlations between VEGF and VTE. Based on 9 SNPs, the circulating VEGF level was positively related to the risk of VTE using inverse variance weighting (IVW) method (odds ratio (OR) = 1.064, 95 % confidence interval (CI), 1.009 – 1.122). Reverse MR analyses showed that genetic liability for VTE was not associated with increased VEGF level (β = -0.021, 95 % CI, -0.087-0.045). Pleiotropy-robust methods indicated no bias in any estimates. Conclusions: Our findings failed to detect coheritability between VEGF and VTE. The suggestive positive effect of the higher VEGF level on the VTE risk may have clinical implications, suggesting that VEGF as a possible predictor and therapeutic target for VTE prevention need to be further warranted

Hemophilia a patients with inhibitors: Mechanistic insights and novel therapeutic implications

The development of coagulation factor VIII (FVIII) inhibitory antibodies is a serious complication in hemophilia A (HA) patients after FVIII replacement therapy. Inhibitors render regular prophylaxis ineffective and increase the risk of morbidity and mortality. Immune tolerance induction (ITI) regimens have become the only clinically proven therapy for eradicating these inhibitors. However, this is a lengthy and costly strategy. For HA patients with high titer inhibitors, bypassing or new hemostatic agents must be used in clinical prophylaxis due to the ineffective ITI regimens. Since multiple genetic and environmental factors are involved in the pathogenesis of inhibitor generation, understanding the mechanisms by which inhibitors develop could help identify critical targets that can be exploited to prevent or eradicate inhibitors. In this review, we provide a comprehensive overview of the recent advances related to mechanistic insights into anti-FVIII antibody development and discuss novel therapeutic approaches for HA patients with inhibitors