Ras Suppressor-1 (RSU1) in Cancer Cell Metastasis: A Tale of a Tumor Suppressor

Cancer is a multifactorial disease responsible for millions of deaths worldwide. It has a strong genetic background, as mutations in oncogenes or tumor suppressor genes contribute to the initiation of cancer development. Integrin signaling as well as the signaling pathway of Ras oncogene, have been long implicated both in carcinogenesis and disease progression. Moreover, they have been involved in the promotion of metastasis, which accounts for the majority of cancer-related deaths. Ras Suppressor-1 (RSU1) was identified as a suppressor of Ras-induced transformation and was shown to localize to cell-extracellular matrix adhesions. Recent findings indicate that its expression is elevated in various cancer types, while its role in regulating metastasis-related cellular processes remains largely unknown. Interestingly, there is no in vivo work in the field to date, and thus, all relevant knowledge stems from in vitro studies. In this review, we summarize recent studies using breast, liver and brain cancer cell lines and highlight the role of RSU1 in regulating cancer cell invasion.

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MiR-212-3p functions as a tumor suppressor gene in group 3 medulloblastoma via targeting nuclear factor I/B (NFIB)

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01299-z ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Naveenkumar Perumal ◽

Ranjana K. Kanchan ◽

David Doss ◽

Noah Bastola ◽

Pranita Atri ◽

...

Keyword(s):

Cell Proliferation ◽

Tumor Suppressor ◽

Cancer Cell ◽

Migration And Invasion ◽

Stem Cell Markers ◽

Cancer Cell Proliferation ◽

Group 3

AbstractHaploinsufficiency of chromosome 17p and c-Myc amplification distinguish group 3 medulloblastomas which are associated with early metastasis, rapid recurrence, and swift mortality. Tumor suppressor genes on this locus have not been adequately characterized. We elucidated the role of miR-212-3p in the pathophysiology of group 3 tumors. First, we learned that miR-212-3p undergoes epigenetic silencing by histone modifications in group 3 tumors. Restoring its expression reduced cancer cell proliferation, migration, colony formation, and wound healing in vitro and attenuated tumor burden and improved survival in vivo. MiR-212-3p also triggered c-Myc destabilization and degradation, leading to elevated apoptosis. We then isolated an oncogenic target of miR-212-3p, i.e. NFIB, a nuclear transcription factor implicated in metastasis and recurrence in various cancers. Increased expression of NFIB was confirmed in group 3 tumors and associated with poor survival. NFIB silencing reduced cancer cell proliferation, migration, and invasion. Concurrently, reduced medullosphere formation and stem cell markers (Nanog, Oct4, Sox2, CD133) were noted. These results substantiate the tumor-suppressive role of miR-212-3p in group 3 MB and identify a novel oncogenic target implicated in metastasis and tumor recurrence.

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The Role of Herbal Bioactive Components in Mitochondria Function and Cancer Therapy

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/3868354 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Fangfang Tao ◽

Yanrong Zhang ◽

Zhiqian Zhang

Keyword(s):

Cancer Therapy ◽

Cancer Cell ◽

Apoptotic Cell ◽

Redox Status ◽

Cancer Therapies ◽

Bioactive Components ◽

Atp Production

Mitochondria are highly dynamic double-membrane organelles which play a well-recognized role in ATP production, calcium homeostasis, oxidation-reduction (redox) status, apoptotic cell death, and inflammation. Dysfunction of mitochondria has long been observed in a number of human diseases, including cancer. Targeting mitochondria metabolism in tumors as a cancer therapeutic strategy has attracted much attention for researchers in recent years due to the essential role of mitochondria in cancer cell growth, apoptosis, and progression. On the other hand, a series of studies have indicated that traditional medicinal herbs, including traditional Chinese medicines (TCM), exert their potential anticancer effects as an effective adjunct treatment for alleviating the systemic side effects of conventional cancer therapies, for reducing the risk of recurrence and cancer mortality and for improving the quality of patients’ life. An amazing feature of these structurally diverse bioactive components is that majority of them target mitochondria to provoke cancer cell-specific death program. The aim of this review is to summarize the in vitro and in vivo studies about the role of these herbs, especially their bioactive compounds in the modulation of the disturbed mitochondrial function for cancer therapy.

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Hypermethylation of DHRS3 as a Novel Tumor Suppressor Involved in Tumor Growth and Prognosis in Gastric Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.624871 ◽

2021 ◽

Vol 9 ◽

Author(s):

Sha Sumei ◽

Kong Xiangyun ◽

Chen Fenrong ◽

Sun Xueguang ◽

Hu Sijun ◽

...

Keyword(s):

Gastric Cancer ◽

Tumor Suppressor ◽

Tumor Growth ◽

Human Cancer ◽

Methylation Status ◽

Ectopic Expression ◽

Survival Times

Background/AimsThe role of DHRS3 in human cancer remains unclear. Our study explored the role of DHRS3 in gastric cancer (GC) and its clinicopathological significance and associated mechanisms.MaterialsBisulfite-assisted genomic sequencing PCR and a Mass-Array system were used to evaluate and quantify the methylation levels of the promoter. The expression levels and biological function of DHRS3 was examined by both in vitro and in vivo assays. A two-way hierarchical cluster analysis was used to classify the methylation profiles, and the correlation between the methylation status of the DHRS3 promoter and the clinicopathological characteristics of GC were then assessed.ResultsThe DHRS3 promoter was hypermethylated in GC samples, while the mRNA and protein levels of DHRS3 were significantly downregulated. Ectopic expression of DHRS3 in GC cells inhibited cell proliferation and migration in vitro, decreased tumor growth in vivo. DHRS3 methylation was correlated with histological type and poor differentiation of tumors. GC patients with high degrees of CpG 9.10 methylation had shorter survival times than those with lower methylation.ConclusionDHRS3 was hypermethylated and downregulated in GC patients. Reduced expression of DHRS3 is implicated in gastric carcinogenesis, which suggests DHRS3 is a tumor suppressor.

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Transcriptional role of p53 in interferon-mediated antiviral immunity

Journal of Experimental Medicine ◽

10.1084/jem.20080383 ◽

2008 ◽

Vol 205 (8) ◽

pp. 1929-1938 ◽

Cited By ~ 130

Author(s):

César Muñoz-Fontela ◽

Salvador Macip ◽

Luis Martínez-Sobrido ◽

Lauren Brown ◽

Joseph Ashour ◽

...

Keyword(s):

Tumor Suppressor ◽

Viral Replication ◽

Viral Infections ◽

Suppressor Gene ◽

Central Component ◽

Type I ◽

Infected Cells

Tumor suppressor p53 is activated by several stimuli, including DNA damage and oncogenic stress. Previous studies (Takaoka, A., S. Hayakawa, H. Yanai, D. Stoiber, H. Negishi, H. Kikuchi, S. Sasaki, K. Imai, T. Shibue, K. Honda, and T. Taniguchi. 2003. Nature. 424:516–523) have shown that p53 is also induced in response to viral infections as a downstream transcriptional target of type I interferon (IFN) signaling. Moreover, many viruses, including SV40, human papillomavirus, Kaposi's sarcoma herpesvirus, adenoviruses, and even RNA viruses such as polioviruses, have evolved mechanisms designated to abrogate p53 responses. We describe a novel p53 function in the activation of the IFN pathway. We observed that infected mouse and human cells with functional p53 exhibited markedly decreased viral replication early after infection. This early inhibition of viral replication was mediated both in vitro and in vivo by a p53-dependent enhancement of IFN signaling, specifically the induction of genes containing IFN-stimulated response elements. Of note, p53 also contributed to an increase in IFN release from infected cells. We established that this p53-dependent enhancement of IFN signaling is dependent to a great extent on the ability of p53 to activate the transcription of IFN regulatory factor 9, a central component of the IFN-stimulated gene factor 3 complex. Our results demonstrate that p53 contributes to innate immunity by enhancing IFN-dependent antiviral activity independent of its functions as a proapoptotic and tumor suppressor gene.

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Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer

Molecular and Cellular Biology ◽

10.1128/mcb.12.3.1387-1395.1992 ◽

1992 ◽

Vol 12 (3) ◽

pp. 1387-1395

Author(s):

M C Goyette ◽

K Cho ◽

C L Fasching ◽

D B Levy ◽

K W Kinzler ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Suppressor ◽

Tumor Suppressor Genes ◽

Loss Of Function ◽

Chromosome 18 ◽

Chromosome 5 ◽

Suppressor Genes ◽

Single Defect

Carcinogenesis is a multistage process that has been characterized both by the activation of cellular oncogenes and by the loss of function of tumor suppressor genes. Colorectal cancer has been associated with the activation of ras oncogenes and with the deletion of multiple chromosomal regions including chromosomes 5q, 17p, and 18q. Such chromosome loss is often suggestive of the deletion or loss of function of tumor suppressor genes. The candidate tumor suppressor genes from these regions are, respectively, MCC and/or APC, p53, and DCC. In order to further our understanding of the molecular and genetic mechanisms involved in tumor progression and, thereby, of normal cell growth, it is important to determine whether defects in one or more of these loci contribute functionally in the progression to malignancy in colorectal cancer and whether correction of any of these defects restores normal growth control in vitro and in vivo. To address this question, we have utilized the technique of microcell-mediated chromosome transfer to introduce normal human chromosomes 5, 17, and 18 individually into recipient colorectal cancer cells. Additionally, chromosome 15 was introduced into SW480 cells as an irrelevant control chromosome. While the introduction of chromosome 17 into the tumorigenic colorectal cell line SW480 yielded no viable clones, cell lines were established after the introduction of chromosomes 15, 5, and 18. Hybrids containing chromosome 18 are morphologically similar to the parental line, whereas those containing chromosome 5 are morphologically distinct from the parental cell line, being small, polygonal, and tightly packed. SW480-chromosome 5 hybrids are strongly suppressed for tumorigenicity, while SW480-chromosome 18 hybrids produce slowly growing tumors in some of the animals injected. Hybrids containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer ot chromosome 18 restored responsiveness to some degree. Our findings indicate that while multiple defects in tumor suppressor genes seem to be required for progression to the malignant state in colorectal cancer, correction of only a single defect can have significant effects in vivo and/or in vitro.

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2, 3-Dihydro-3β-methoxy Withaferin-A Lacks Anti-Metastasis Potency: Bioinformatics and Experimental Evidences

Scientific Reports ◽

10.1038/s41598-019-53568-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Anupama Chaudhary ◽

Rajkumar S. Kalra ◽

Vidhi Malik ◽

Shashank P. Katiyar ◽

Durai Sundar ◽

...

Keyword(s):

Cell Migration ◽

Cancer Cells ◽

Cancer Cell ◽

Human Cancer ◽

Effector Proteins ◽

Withaferin A ◽

Migration And Invasion ◽

Cell Metastasis

AbstractWithaferin-A is a withanolide, predominantly present in Ashwagandha (Withania somnifera). It has been shown to possess anticancer activity in a variety of human cancer cells in vitro and in vivo. Molecular mechanism of such cytotoxicity has not yet been completely understood. Withaferin-A and Withanone were earlier shown to activate p53 tumor suppressor and oxidative stress pathways in cancer cells. 2,3-dihydro-3β-methoxy analogue of Withaferin-A (3βmWi-A) was shown to lack cytotoxicity and well tolerated at higher concentrations. It, on the other hand, protected normal cells against oxidative, chemical and UV stresses through induction of anti-stress and pro-survival signaling. We, in the present study, investigated the effect of Wi-A and 3βmWi-A on cell migration and metastasis signaling. Whereas Wi-A binds to vimentin and heterogeneous nuclear ribonucleoprotein K (hnRNP-K) with high efficacy and downregulates its effector proteins, MMPs and VEGF, involved in cancer cell metastasis, 3βmWi-A was ineffective. Consistently, Wi-A, and not 3βmWi-A, caused reduction in cytoskeleton proteins (Vimentin, N-Cadherin) and active protease (u-PA) that are essential for three key steps of cancer cell metastasis (EMT, increase in cell migration and invasion).

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Exploiting GRK2 Inhibition as a Therapeutic Option in Experimental Cancer Treatment: Role of p53-Induced Mitochondrial Apoptosis

Cancers ◽

10.3390/cancers12123530 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3530

Author(s):

Jessica Gambardella ◽

Antonella Fiordelisi ◽

Gaetano Santulli ◽

Michele Ciccarelli ◽

Federica Andrea Cerasuolo ◽

...

Keyword(s):

Cell Proliferation ◽

Cancer Cell ◽

Nude Mice ◽

Specific Inhibitor ◽

Cancer Cell Proliferation ◽

In Vivo Models ◽

P53 Expression

The involvement of GRK2 in cancer cell proliferation and its counter-regulation of p53 have been suggested in breast cancer even if the underlying mechanism has not yet been elucidated. Furthermore, the possibility to pharmacologically inhibit GRK2 to delay cancer cell proliferation has never been explored. We investigated this possibility by setting up a study that combined in vitro and in vivo models to underpin the crosstalk between GRK2 and p53. To reach this aim, we took advantage of the different expression of p53 in cell lines of thyroid cancer (BHT 101 expressing p53 and FRO cells, which are p53-null) in which we overexpressed or silenced GRK2. The pharmacological inhibition of GRK2 was achieved using the specific inhibitor KRX-C7. The in vivo study was performed in Balb/c nude mice, where we treated BHT-101 or FRO-derived tumors with KRX-C7. In our in vitro model, FRO cells were unaffected by GRK2 expression levels, whereas BHT-101 cells were sensitive, thus suggesting a role for p53. The regulation of p53 by GRK2 is due to phosphorylative events in Thr-55, which induce the degradation of p53. In BHT-101 cells, the pharmacologic inhibition of GRK2 by KRX-C7 increased p53 levels and activated apoptosis through the mitochondrial release of cytochrome c. These KRX-C7-mediated events were also confirmed in cancer allograft models in nude mice. In conclusion, our data showed that GRK2 counter-regulates p53 expression in cancer cells through a kinase-dependent activity. Our results further corroborate the anti-proliferative role of GRK2 inhibitors in p53-sensitive tumors and propose GRK2 as a therapeutic target in selected cancers.

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Functional genetic encoding of sulfotyrosine in mammalian cells

Nature Communications ◽

10.1038/s41467-020-18629-9 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Xinyuan He ◽

Yan Chen ◽

Daisy Guiza Beltran ◽

Maia Kelly ◽

Bin Ma ◽

...

Keyword(s):

Mammalian Cells ◽

Biochemical Characterization ◽

Trna Synthetase ◽

Functional Verification ◽

Cellular Processes ◽

Genetic Encoding ◽

Efficient Expression

Abstract Protein tyrosine O-sulfation (PTS) plays a crucial role in extracellular biomolecular interactions that dictate various cellular processes. It also involves in the development of many human diseases. Regardless of recent progress, our current understanding of PTS is still in its infancy. To promote and facilitate relevant studies, a generally applicable method is needed to enable efficient expression of sulfoproteins with defined sulfation sites in live mammalian cells. Here we report the engineering, in vitro biochemical characterization, structural study, and in vivo functional verification of a tyrosyl-tRNA synthetase mutant for the genetic encoding of sulfotyrosine in mammalian cells. We further apply this chemical biology tool to cell-based studies on the role of a sulfation site in the activation of chemokine receptor CXCR4 by its ligand. Our work will not only facilitate cellular studies of PTS, but also paves the way for economical production of sulfated proteins as therapeutic agents in mammalian systems.

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Mortaparib, a novel dual inhibitor of mortalin and PARP1, is a potential drug candidate for ovarian and cervical cancers

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1500-9 ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 1

Author(s):

Jayarani F. Putri ◽

Priyanshu Bhargava ◽

Jaspreet Kaur Dhanjal ◽

Tomoko Yaguchi ◽

Durai Sundar ◽

...

Keyword(s):

Tumor Suppressor ◽

Cancer Cells ◽

Cancer Cell ◽

Growth Arrest ◽

Suppressor Activity ◽

Dual Inhibitor ◽

Tumor Suppressor Activity ◽

And Migration

Abstract Background Mortalin is enriched in a large variety of cancers and has been shown to contribute to proliferation and migration of cancer cells in multiple ways. It has been shown to bind to p53 protein in cell cytoplasm and nucleus causing inactivation of its tumor suppressor activity in cancer cells. Several other activities of mortalin including mitochondrial biogenesis, ATP production, chaperoning, anti-apoptosis contribute to pro-proliferative and migration characteristics of cancer cells. Mortalin-compromised cancer cells have been shown to undergo apoptosis in in vitro and in vivo implying that it could be a potential target for cancer therapy. Methods We implemented a screening of a chemical library for compounds with potential to abrogate cancer cell specific mortalin-p53 interactions, and identified a new compound (named it as Mortaparib) that caused nuclear enrichment of p53 and shift in mortalin from perinuclear (typical of cancer cells) to pancytoplasmic (typical of normal cells). Biochemical and molecular assays were used to demonstrate the effect of Mortaparib on mortalin, p53 and PARP1 activities. Results Molecular homology search revealed that Mortaparib is a novel compound that showed strong cytotoxicity to ovarian, cervical and breast cancer cells. Bioinformatics analysis revealed that although Mortaparib could interact with mortalin, its binding with p53 interaction site was not stable. Instead, it caused transcriptional repression of mortalin leading to activation of p53 and growth arrest/apoptosis of cancer cells. By extensive computational and experimental analyses, we demonstrate that Mortaparib is a dual inhibitor of mortalin and PARP1. It targets mortalin, PARP1 and mortalin-PARP1 interactions leading to inactivation of PARP1 that triggers growth arrest/apoptosis signaling. Consistent with the role of mortalin and PARP1 in cancer cell migration, metastasis and angiogenesis, Mortaparib-treated cells showed inhibition of these phenotypes. In vivo tumor suppression assays showed that Mortaparib is a potent tumor suppressor small molecule and awaits clinical trials. Conclusion These findings report (i) the discovery of Mortaparib as a first dual inhibitor of mortalin and PARP1 (both frequently enriched in cancers), (ii) its molecular mechanism of action, and (iii) in vitro and in vivo tumor suppressor activity that emphasize its potential as an anticancer drug.

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