MIIP, a cytoskeleton regulator that blocks cell migration and invasion, delays mitosis, and suppresses tumorogenesis

The migration and invasion inhibitory protein (MIIP) was initially discovered in a yeast two-hybrid screen for proteins that interact and inhibit the migration and invasion-promoting protein insulin-like growth factor binding protein 2 (IGFBP2). Recent studies have shown that MIIP not only modulates IGFBP2 but also regulates microtubule by binding to and inhibiting HDAC6, a class 2 histone deacetylase that deacetylates α-tubulin, heat-shock protein 90 (HSP90), and cortactin. In addition, MIIP also regulates the mitosis checkpoint, another microtubule-associated process. The location of the MIIP gene in chromosomal region 1p36, a commonly deleted region in a broad spectrum of human cancers, and the observation that MIIP attenuates tumorigenesis in a mouse model suggest that it functions as a tumor-suppressor gene. This review summarizes the recent progress in characterizing this novel protein, which regulates cell migration and mitosis, two processes that rely on the highly coordinated dynamics of the microtubule and cytoskeleton systems.     

Deoxyelephantopin and Its Isomer Isodeoxyelephantopin: Anti-Cancer Natural Products with Multiple Modes of Action

Cancer is a leading cause of morbidity and mortality worldwide. The development of cancer involves aberrations in multiple pathways, representing promising targets for anti-cancer drug discovery. Natural products are regarded as a rich source for developing anti-cancer therapies due to their unique structures and favorable pharmacology and toxicology profiles. Deoxyelephantopin and isodeoxyelephantopin, sesquiterpene lactone compounds, are major components of Elephantopus scaber and Elephantopus carolinianus, which have long been used as traditional medicines to treat multiple ailments, including liver diseases, diabetes, bronchitis, fever, diarrhea, dysentery, cancer, renal disorders, and inflammation-associated diseases. Recently, deoxyelephantopin and isodeoxyelephantopin have been extensively explored for their anti-cancer activities. This review summarizes and discusses the anti-cancer activities of deoxyelephantopin and isodeoxyelephantopin, with an emphasis on their modes of action and molecular targets. Both compounds disrupt several processes involved in cancer progression by targeting multiple signaling pathways deregulated in cancers, including cell cycle and proliferation, cell survival, autophagy, and invasion pathways. Future directions of research on these two compounds towards anti-cancer drug development are discussed.     

Structural,molecular, and functional insights into Schlafen proteins

Schlafen (SLFN) genes belong to a vertebrate gene family encoding proteins with high sequence homology. However, each SLFN is functionally divergent and differentially expressed in various tissues and species, showing a wide range of expression in cancer and normal cells. SLFNs are involved in various cellular and tissue-specific processes, including DNA replication, proliferation, immune and interferon responses, viral infections, and sensitivity to DNA-targeted anticancer agents. The fundamental molecular characteristics of SLFNs and their structures are beginning to be elucidated. Here, we review recent structural insights into the N-terminal, middle and C-terminal domains (N-, M-, and C-domains, respectively) of human SLFNs and discuss the current understanding of their biological roles. We review the distinct molecular activities of SLFN11, SLFN5, and SLFN12 and the relevance of SLFN11 as a predictive biomarker in oncology.Subject terms: Cancer, Cancer therapy     

Mitotic protein kinase-driven crosstalk of machineries for mitosis and metastasis

Accumulating evidence indicates that mitotic protein kinases are involved in metastatic migration as well as tumorigenesis. Protein kinases and cytoskeletal proteins play a role in the efficient release of metastatic cells from a tumor mass in the tumor microenvironment, in addition to playing roles in mitosis. Mitotic protein kinases, including Polo-like kinase 1 (PLK1) and Aurora kinases, have been shown to be involved in metastasis in addition to cell proliferation and tumorigenesis, depending on the phosphorylation status and cellular context. Although the genetic programs underlying mitosis and metastasis are different, the same protein kinases and cytoskeletal proteins can participate in both mitosis and cell migration/invasion, resulting in migratory tumors. Cytoskeletal remodeling supports several cellular events, including cell division, movement, and migration. Thus, understanding the contributions of cytoskeletal proteins to the processes of cell division and metastatic motility is crucial for developing efficient therapeutic tools to treat cancer metastases. Here, we identify mitotic kinases that function in cancer metastasis as well as tumorigenesis. Several mitotic kinases, namely, PLK1, Aurora kinases, Rho-associated protein kinase 1, and integrin-linked kinase, are considered in this review, as an understanding of the shared machineries between mitosis and metastasis could be helpful for developing new strategies to treat cancer.Subject terms: Oncogenes, Mitosis, Metastasis     

Glutamine reliance in cell metabolism

As knowledge of cell metabolism has advanced, glutamine has been considered an important amino acid that supplies carbon and nitrogen to fuel biosynthesis. A recent study provided a new perspective on mitochondrial glutamine metabolism, offering mechanistic insights into metabolic adaptation during tumor hypoxia, the emergence of drug resistance, and glutaminolysis-induced metabolic reprogramming and presenting metabolic strategies to target glutamine metabolism in cancer cells. In this review, we introduce the various biosynthetic and bioenergetic roles of glutamine based on the compartmentalization of glutamine metabolism to explain why cells exhibit metabolic reliance on glutamine. Additionally, we examined whether glutamine derivatives contribute to epigenetic regulation associated with tumorigenesis. In addition, in discussing glutamine transporters, we propose a metabolic target for therapeutic intervention in cancer.Subject terms: Cancer metabolism, Metabolomics, Cancer metabolism, Metabolomics     

Synthesis of Ras proteins and their application in biofunctional studies

We summarized the developed strategies including chemical total synthesis, biosynthesis and semi-synthesis for producing Ras proteins with modification and their application in biological studies.     

The Molecular Basis of Different Approaches for the Study of Cancer Stem Cells and the Advantages and Disadvantages of a Three-Dimensional Culture

Cancer stem cells (CSCs) are a rare tumor subpopulation with high differentiation, proliferative and tumorigenic potential compared to the remaining tumor population. CSCs were first discovered by Bonnet and Dick in 1997 in acute myeloid leukemia. The identification and isolation of these cells in this pioneering study were carried out through the flow cytometry, exploiting the presence of specific cell surface molecular markers (CD34⁺/CD38⁻). In the following years, different strategies and projects have been developed for the study of CSCs, which are basically divided into surface markers assays and functional assays; some of these techniques also allow working with a cellular model that better mimics the tumor architecture. The purpose of this mini review is to summarize and briefly describe all the current methods used for the identification, isolation and enrichment of CSCs, describing, where possible, the molecular basis, the advantages and disadvantages of each technique with a particular focus on those that offer a three-dimensional culture.     

Pan-cancer analysis of DNA epigenetic modifications by hydrophilic interaction liquid chromatography-tandem mass spectrometry

Accumulating evidence in recent years indicates that DNA methylation (5-methyl-2′-deoxycytidine, 5-mdC) and hydroxymethylation (5-hydroxymethyl-2′-deoxycytidine, 5-hmdC) have been implicated in various biological processes, and the aberrations of these DNA cytosine modifications is tightly associated with cancer. N⁶-methyl-2′-deoxyadenosine (m⁶dA), as a newly discovered epigenetic modification in genome of mammals, has been demonstrated to play vital regulatory roles in tumorigenesis. However, the content information of m⁶dA in human tumor tissues is still limited and pan-cancer analysis of these DNA epigenetic modifications is lacked. Herein, we developed a sensitive and robust stable isotope-diluted hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) method for accurate quantification of m⁶dA, 5-mdC and 5-hmdC in genomic DNA from 82 pairs of human tumor tissues and matched tumor-adjacent normal tissues. The types of tumors included esophagus cancer, lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, stromal tumor and colorectal cancer. Compared to the normal tissues, we revealed the level of m⁶dA was increased in tumor tissues of esophagus cancer, lung cancer and liver cancer, whereas the level of m⁶dA was diminished in tumor tissues of pancreatic cancer and gastric cancer; while the contents of 5-mdC and 5-hmdC exhibited significant decrease in tumor tissues of most types of cancer. It is worth noting that we revealed, for the first time, the content of genomic m⁶dA in pancreatic cancer, stromal tumor and colorectal cancer. The significant changes of these DNA epigenetic modifications indicate they may serve as indicators of cancers. In addition, this study will benefit for better understanding of the regulatory roles of these DNA epigenetic modifications in cancers.     

Thieno[2,3-c]pyridazine Derivatives: Synthesis and Antimicrobial Activity

Thieno[2,3-c]pyridazine 2 was selected as the starting material for the synthesis of some novel 5-arylidene amino and 5-thiazolidine derivatives. The structures of the synthesized compounds were elucidated by elemental analyses and spectral data. The antimicrobial and antifungal activities of the newly synthesized products were measured against some microorganisms.     

Gastrointestinal cancer organoids—applications in basic and translational cancer research

Cancer is a major health problem and a leading cause of death worldwide. Early cancer detection and continuous changes in treatment strategies have improved overall patient survival. The recent development of targeted drugs offers new opportunities for personalized cancer treatment. Nevertheless, individualized treatment is accompanied by the need for biomarkers predicting the response of a patient to a certain drug. One of the most promising breakthroughs in recent years that might help to overcome this problem is the organoid technology. Organoid cultures exhibit self-renewal capacity, self-organization, and long-term proliferation, while recapitulating many aspects of their primary tissue. Generated patient-derived organoid (PDO) libraries constitute “living” biobanks, allowing the in-depth analysis of tissue function, development, tumor initiation, and cancer pathobiology. Organoids can be derived from all gastrointestinal tissues, including esophageal, gastric, liver, pancreatic, small intestinal and colorectal tissues, and cancers of these tissues. PDOs are amenable to various techniques, including sequencing analyses, drug screening, targeted therapy testing, tumor microenvironment studies, and genetic engineering capabilities. In this review, we discuss the different applications of gastrointestinal organoids in basic cancer biology and clinical translation.Subject terms: Gastrointestinal cancer, Cancer models     

Synthesis,in vitro biological evaluation and in silico docking studies of new quinazolin-2,4-dione analogues as possible anticarcinoma agents

Today, cancer is considered as one of the major reasons of death in human beings worldwide. We reported herein the synthesis, anticancer activity, and in silico docking studies of a series of nine quinazolindione-based scaffolds bearing pyrimidine, pyridine, pyran, and pyrazole moieties ( 1 - 9 ) through Michael addition, Vilsmeier-Haack, Claisen-Schmidt, and nucleophilic addition reactions. The chemical structures of the newly prepared compounds were ascertained by means of their spectral analysis techniques like IR, ¹H-nuclear magnetic resonance (NMR), ¹³C-NMR, mass spectroscopy, and elemental analysis. This work was conducted to investigate the implication of Rho7 protein in breast and hepatocellular cancer cells aggressively. MCF-7 and HepG2 cells have been selected as models for the effect of protein expression on breast and hepatocellular cancers cell growth. All prepared compounds were biologically evaluated for their antiproliferative efficacy on hepatic cancer cell lines (HepG2) and breast cancer cell lines (MCF-7); also, their effects on normal cell lines (BALB/3T3) were studied. Moreover, in silico molecular docking studies were studied for the compounds against the binding site of Homo sapiens Rho7 protein. The pharmacokinetic properties of the newer compounds were also evaluated using various computational tools. The compounds showed interesting interactions with satisfactory docking scores to the target Rho7; thus, they may act as promising potent drug candidates against cancer.     

Genesis and Mechanism of Some Cancer Types and an Overview on the Role of Diet and Nutrition in Cancer Prevention

Cancer is a major disease with a high mortality rate worldwide. In many countries, cancer is considered to be the second most common cause of death after cardiovascular disease. The clinical management of cancer continues to be a challenge as conventional treatments, such as chemotherapy and radiation therapy, have limitations due to their toxicity profiles. Unhealthy lifestyle and poor dietary habits are the key risk factors for cancer; having a healthy diet and lifestyle may minimize the risk. Epidemiological studies have shown that a high fruit and vegetable intake in our regular diet can effectively reduce the risk of developing certain types of cancers due to the high contents of antioxidants and phytochemicals. In vitro and in vivo studies have shown that phytochemicals exert significant anticancer effects due to their free radical scavenging capacity potential. There has been extensive research on the protective effects of phytochemicals in different types of cancers. This review attempts to give an overview of the etiology of different types of cancers and assesses the role of phytonutrients in the prevention of cancers, which makes the present review distinct from the others available.     

Nuclear annexin II negatively regulates growth of LNCaP cells and substitution of ser 11 and 25 to glu prevents nucleo-cytoplasmic shuttling of annexin II

Background  

Annexin II heavy chain (also called p36, calpactin I) is lost in prostate cancers and in a majority of prostate intraepithelial neoplasia (PIN). Loss of annexin II heavy chain appears to be specific for prostate cancer since overexpression of annexin II is observed in a majority of human cancers, including pancreatic cancer, breast cancer and brain tumors. Annexin II exists as a heterotetramer in complex with a protein ligand p11 (S100A10), and as a monomer. Diverse cellular functions are proposed for the two forms of annexin II. The monomer is involved in DNA synthesis. A leucine-rich nuclear export signal (NES) in the N-terminus of annexin II regulates its nuclear export by the CRM1-mediated nuclear export pathway. Mutation of the NES sequence results in nuclear retention of annexin II.     

Therapeutic Targeting of the NRF2 Signaling Pathway in Cancer

Cancer is one of the most fatal diseases with an increasing incidence and mortality all over the world. Thus, there is an urgent need for novel therapies targeting major cancer-related pathways. Nuclear factor-erythroid 2-related factor 2 (NRF2) and its major negative modulator Kelch-like ECH-associated protein 1 (KEAP1) are main players of the cellular defense mechanisms against internal and external cell stressors. However, NRF2/KEAP1 signaling pathway is dysregulated in various cancers, thus promoting tumor cell survival and metastasis. In the present review, we discuss the mechanisms of normal and deregulated NRF2 signaling pathway focusing on its cancer-related functions. We further explore activators and inhibitors of this pathway as cancer targeting drug candidates in order to provide an extensive background on the subject.     

The disubstituted adamantyl derivative LW1564 inhibits the growth of cancer cells by targeting mitochondrial respiration and reducing hypoxia-inducible factor (HIF)-1α accumulation

Targeting cancer metabolism has emerged as an important cancer therapeutic strategy. Here, we describe the synthesis and biological evaluation of a novel class of hypoxia-inducible factor (HIF)-1α inhibitors, disubstituted adamantyl derivatives. One such compound, LW1564, significantly suppressed HIF-1α accumulation and inhibited the growth of various cancer cell lines, including HepG2, A549, and HCT116. Measurements of the oxygen consumption rate (OCR) and ATP production rate revealed that LW1564 suppressed mitochondrial respiration, thereby increasing the intracellular oxygen concentration to stimulate HIF-1α degradation. LW1564 also significantly decreased overall ATP levels by inhibiting mitochondrial electron transport chain (ETC) complex I and downregulated mammalian target of rapamycin (mTOR) signaling by increasing the AMP/ATP ratio, which increased AMP-activated protein kinase (AMPK) phosphorylation. Consequently, LW1564 promoted the phosphorylation of acetyl-CoA carboxylase, which inhibited lipid synthesis. In addition, LW1564 significantly inhibited tumor growth in a HepG2 mouse xenograft model. Taken together, the results indicate that LW1564 inhibits the growth of cancer cells by targeting mitochondrial ETC complex I and impairing cancer cell metabolism. We, therefore, suggest that LW1564 may be a potent therapeutic agent for a subset of cancers that rely on oxidative phosphorylation for ATP generation.Subject terms: Cancer metabolism, Cancer metabolism, Drug development     

Mitochondrial Sirtuins in Skin and Skin Cancers

Mammalian sirtuins (SIRTs 1-7) are a family of NAD+-dependent deacetylases with distinct subcellular localization and biological functions that regulate various important cellular processes. Among these, SIRTs -3, -4 and -5 are located in the mitochondria and have been implicated in caloric restriction, oxidative stress, aging and various human diseases. Emerging evidence has found dysregulation of mitochondrial sirtuins in multiple dermatological conditions, including responses to ultraviolet radiation (UVR), suggesting their importance in maintaining skin health. In this review, we discuss the roles and implications of mitochondrial sirtuins in cutaneous cellular processes, and their emerging potential as a target for the management of skin diseases, including skin cancer. Among mitochondrial sirtuins, SIRT3 is the most studied and linked to multiple skin conditions and diseases (keratinocyte differentiation, wound healing, chronological aging, UVR and ozone response, systemic sclerosis, melanoma, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)). SIRT4 has been connected to keratinocyte differentiation, chronological aging, UVR response, alopecia, BCC and SCC. Further, SIRT5 has been associated with keratinocyte differentiation, melanoma, BCC and SCC. Overall, while there is compelling evidence for the involvement of mitochondrial sirtuins in skin, additional detailed studies are needed to understand their exact roles in skin and skin cancers.     

Protein Prenylation: An (Almost) Comprehensive Overview on Discovery History, Enzymology, and Significance in Physiology and Disease

Summary. Since 1979, when prenylation has been first discovered as chemical oddity of a yeast mating factor, the two forms of this posttranslational modification of proteins (farnesylation and geranylgeranylation) have been found as wide spread among proteins from Eukarya and their viruses. This review attempts to summarize as comprehensively as possible the enzymological processes of prenylation and the various aspects of their biological significance. The substrate proteins of prenyltransferases are known to carry a sequence signal composed of a cysteine-containing 4–5 residue stretch at the utmost C-terminal end that is N-terminally preceded by a flexible and polar linker region of ca. 10 residues. Postprenylation processing of substrate proteins can involve C-terminal proteolysis, C-terminal carboxyl methylation, and other steps of maturation. The prenyl anchor functions as module for membrane attachment or for protein–protein interaction. Prenyl anchor carrying proteins fulfill a large array of functions in signaling and regulation of cellular processes. Therefore, they are involved in the pathogenesis of a variety of human diseases, the most prominent one being cancer. Farnesyltransferase inhibitors show surprisingly high efficiency in controlling tumor growth in model systems but, so far, clinical trials with human patients have remained without the desired success. Interference into prenylation pathways appears also a promising treatment principle in a variety of parasitic diseases.