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1.
Akt scaffold proteins: the key to controlling specificity of Akt signaling.
Bao, F, Hao, P, An, S, Yang, Y, Liu, Y, Hao, Q, Ejaz, M, Guo, XX, Xu, TR
American journal of physiology. Cell physiology. 2021;(3):C429-C442
Abstract
The phosphatidylinositol 3-kinase-Akt signaling pathway plays an essential role in regulating cell proliferation and apoptosis. Akt kinase is at the center of this signaling pathway and interacts with a variety of proteins. Akt is overexpressed in almost 80% of tumors. However, inhibiting Akt has serious clinical side effects so is not a suitable treatment for cancer. During recent years, Akt scaffold proteins have received increasing attention for their ability to regulate Akt signaling and have emerged as potential targets for cancer therapy. In this paper, we categorize Akt kinase scaffold proteins into four groups based on their cellular location: membrane-bound activator and inhibitor, cytoplasm, and endosome. We describe how these scaffolds interact with Akt kinase, how they affect Akt activity, and how they regulate the specificity of Akt signaling. We also discuss the clinical application of Akt scaffold proteins as targets for cancer therapy.
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2.
New promising developments for potential therapeutic applications of high-dose ascorbate as an anticancer drug.
Testa, U, Pelosi, E, Castelli, G
Hematology/oncology and stem cell therapy. 2021;(3):179-191
Abstract
Vitamin C (ascorbate) is an essential dietary requirement, with fundamental redox, anti-oxidant functions at physiologic concentrations. Vitamin C is a cofactor for Fe2+ and 2-oxoglutarate-dependent dioxygenases, englobing large families of enzymes, including also epigenetic regulators of DNA and histone methylation. Importantly, vitamin C is involved in the control of the activity of TET (ten-eleven translocation) enzymes, key epigenetic regulators. For this spectrum of activities, often involving pathways deregulated in cancer cells, vitamin C possesses some pharmacologic activities that can be exploited in anticancer therapy. In particular, the capacity of pharmacological doses of vitamin C to target redox imbalance and to rescue deregulated epigenetic program observed in some cancer cells represents a consistent therapeutic potentiality. Several recent studies have identified some cancer subsets that could benefit from the pharmacological activities of vitamin C. The identification of these potentially responsive patients will help to carefully define controlled clinical trials aiming to evaluate the anticancer activity of Vitamin C.
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3.
Autophagy and Extracellular Vesicles, Connected to rabGTPase Family, Support Aggressiveness in Cancer Stem Cells.
Brunel, A, Bégaud, G, Auger, C, Durand, S, Battu, S, Bessette, B, Verdier, M
Cells. 2021;(6)
Abstract
Even though cancers have been widely studied and real advances in therapeutic care have been made in the last few decades, relapses are still frequently observed, often due to therapeutic resistance. Cancer Stem Cells (CSCs) are, in part, responsible for this resistance. They are able to survive harsh conditions such as hypoxia or nutrient deprivation. Autophagy and Extracellular Vesicles (EVs) secretion are cellular processes that help CSC survival. Autophagy is a recycling process and EVs secretion is essential for cell-to-cell communication. Their roles in stemness maintenance have been well described. A common pathway involved in these processes is vesicular trafficking, and subsequently, regulation by Rab GTPases. In this review, we analyze the role played by Rab GTPases in stemness status, either directly or through their regulation of autophagy and EVs secretion.
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4.
Targeting SUMO Signaling to Wrestle Cancer.
Kroonen, JS, Vertegaal, ACO
Trends in cancer. 2021;(6):496-510
Abstract
The small ubiquitin-like modifier (SUMO) signaling cascade is critical for gene expression, genome integrity, and cell cycle progression. In this review, we discuss the important role SUMO may play in cancer and how to target SUMO signaling. Recently developed small molecule inhibitors enable therapeutic targeting of the SUMOylation pathway. Blocking SUMOylation not only leads to reduced cancer cell proliferation but also to an increased antitumor immune response by stimulating interferon (IFN) signaling, indicating that SUMOylation inhibitors have a dual mode of action that can be employed in the fight against cancer. The search for tumor types that can be treated with SUMOylation inhibitors is ongoing. Employing SUMO conjugation inhibitory drugs in the years to come has potential as a new therapeutic strategy.
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5.
Tumor Suppressors Having Oncogenic Functions: The Double Agents.
Datta, N, Chakraborty, S, Basu, M, Ghosh, MK
Cells. 2020;(1)
Abstract
Cancer progression involves multiple genetic and epigenetic events, which involve gain-of-functions of oncogenes and loss-of-functions of tumor suppressor genes. Classical tumor suppressor genes are recessive in nature, anti-proliferative, and frequently found inactivated or mutated in cancers. However, extensive research over the last few years have elucidated that certain tumor suppressor genes do not conform to these standard definitions and might act as "double agents", playing contrasting roles in vivo in cells, where either due to haploinsufficiency, epigenetic hypermethylation, or due to involvement with multiple genetic and oncogenic events, they play an enhanced proliferative role and facilitate the pathogenesis of cancer. This review discusses and highlights some of these exceptions; the genetic events, cellular contexts, and mechanisms by which four important tumor suppressors-pRb, PTEN, FOXO, and PML display their oncogenic potentials and pro-survival traits in cancer.
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6.
MicroRNAs Determining Carcinogenesis by Regulating Oncogenes and Tumor Suppressor Genes During Cell Cycle.
Fasoulakis, Z, Daskalakis, G, Diakosavvas, M, Papapanagiotou, I, Theodora, M, Bourazan, A, Alatzidou, D, Pagkalos, A, Kontomanolis, EN
MicroRNA (Shariqah, United Arab Emirates). 2020;(2):82-92
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Abstract
AIM: To provide a review considering microRNAs regulating oncogenes and tumor suppressor genes during the different stages of cell cycle, controlling carcinogenesis. METHODS The role of microRNAs involved as oncogenes' and tumor suppressor genes' regulators in cancer was searched in the relevant available literature in MEDLINE, including terms such as "microRNA", "oncogenes", "tumor suppressor genes", "metastasis", "cancer" and others. RESULTS MicroRNAs determine the expression levels of multiple cell cycle regulators, such as cyclins, cyclin dependent kinases and other major cell cycle activators including retinoblastoma 1 (RB- 1) and p53, resulting in alteration and promotion/inhibition of the cell cycle. CONCLUSION MicroRNAs are proven to have a key role in cancer pathophysiology by altering the expression profile of different regulator proteins during cell division cycle and DNA replication. Thus, by acting as oncogenes and tumor suppressor genes, they can either promote or inhibit cancer development and formation, revealing their innovative role as biomarkers and therapeutic tools.
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7.
Targeting vasculogenic mimicry by phytochemicals: A potential opportunity for cancer therapy.
Haiaty, S, Rashidi, MR, Akbarzadeh, M, Maroufi, NF, Yousefi, B, Nouri, M
IUBMB life. 2020;(5):825-841
Abstract
Vasculogenic mimicry (VM) is regarded as a process where very aggressive cancer cells generate vascular-like patterns without the presence of endothelial cells. It is considered as the main mark of malignant cancer and has pivotal role in cancer metastasis and progression in various types of cancers. On the other hand, resistance to the antiangiogenesis therapies leads to the cancer recurrence. Therefore, development of novel chemotherapies and their combinations is urgently needed for abolition of VM structures and also for better tumor therapy. Hence, identifying compounds that target VM structures might be superior therapeutic factors for cancers treatment and controlling the recurrence and metastasis. In recent times, naturally occurring compounds, especially phytochemicals have obtained great attention due to their safe properties. Phytochemicals are also capable of targeting VM structure and also their main signaling pathways. Consequently, in this review article, we illustrated key signaling pathways in VM, and the phytochemicals that affect these structures including curcumin, genistein, lycorine, luteolin, columbamine, triptolide, Paris polyphylla, dehydroeffusol, jatrorrhizine hydrochloride, grape seed proanthocyanidins, resveratrol, isoxanthohumol, dehydrocurvularine, galiellalactone, oxacyclododecindione, brucine, honokiol, ginsenoside Rg3, and norcantharidin. The recognition of these phytochemicals and their safety profile may lead to new therapeutic agents' development for VM elimination in different types of tumors.
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8.
Flavonoids as Epigenetic Modulators for Prostate Cancer Prevention.
Izzo, S, Naponelli, V, Bettuzzi, S
Nutrients. 2020;(4)
Abstract
Prostate cancer (PCa) is a multifactorial disease with an unclear etiology. Due to its high prevalence, long latency, and slow progression, PCa is an ideal target for chemoprevention strategies. Many research studies have highlighted the positive effects of natural flavonoids on chronic diseases, including PCa. Different classes of dietary flavonoids exhibit anti-oxidative, anti-inflammatory, anti-mutagenic, anti-aging, cardioprotective, anti-viral/bacterial and anti-carcinogenic properties. We overviewed the most recent evidence of the antitumoral effects exerted by dietary flavonoids, with a special focus on their epigenetic action in PCa. Epigenetic alterations have been identified as key initiating events in several kinds of cancer. Many dietary flavonoids have been found to reverse DNA aberrations that promote neoplastic transformation, particularly for PCa. The epigenetic targets of the actions of flavonoids include oncogenes and tumor suppressor genes, indirectly controlled through the regulation of epigenetic enzymes such as DNA methyltransferase (DNMT), histone acetyltransferase (HAT), and histone deacetylase (HDAC). In addition, flavonoids were found capable of restoring miRNA and lncRNA expression that is altered during diseases. The optimization of the use of flavonoids as natural epigenetic modulators for chemoprevention and as a possible treatment of PCa and other kinds of cancers could represent a promising and valid strategy to inhibit carcinogenesis and fight cancer.
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9.
Carotenoids in Cancer Metastasis-Status Quo and Outlook.
Koklesova, L, Liskova, A, Samec, M, Zhai, K, Abotaleb, M, Ashrafizadeh, M, Brockmueller, A, Shakibaei, M, Biringer, K, Bugos, O, et al
Biomolecules. 2020;(12)
Abstract
Metastasis represents a major obstacle in cancer treatment and the leading cause of cancer-related deaths. Therefore, the identification of compounds targeting the multi-step and complex process of metastasis could improve outcomes in the management of cancer patients. Carotenoids are naturally occurring pigments with a plethora of biological activities. Carotenoids exert a potent anti-cancer capacity in various cancer models in vitro and in vivo, mediated by the modulation of signaling pathways involved in the migration and invasion of cancer cells and metastatic progression, including key regulators of the epithelial-mesenchymal transition and regulatory molecules, such as matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), urokinase plasminogen activator (uPA) and its receptor (uPAR), hypoxia-inducible factor-1α (HIF-1α), and others. Moreover, carotenoids modulate the expression of genes associated with cancer progression and inflammatory processes as key mediators of the complex process involved in metastasis. Nevertheless, due to the predominantly preclinical nature of the known anti-tumor effects of carotenoids, and unclear results from certain carotenoids in specific cancer types and/or specific parts of the population, a precise analysis of the anti-cancer effects of carotenoids is essential. The identification of carotenoids as effective compounds targeting the complex process of cancer progression could improve the outcomes of advanced cancer patients.
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10.
ZFAS1: A novel vital oncogenic lncRNA in multiple human cancers.
He, A, He, S, Li, X, Zhou, L
Cell proliferation. 2019;(1):e12513
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Abstract
Long noncoding RNAs (lncRNAs) are a class of noncoding, endogenous, single-stranded RNAs longer than 200 nucleotides in length that are transcribed by RNA polymerase II. Mounting evidence has indicated that lncRNAs play key roles in several physiological and pathological processes by modifying gene expression at the transcriptional, posttranscriptional, epigenetic, and translation levels. Many reports have demonstrated that lncRNAs function as potential oncogene or tumour suppressors and thus play vital regulatory roles in tumourigenesis and tumour progression. ZNFX1 antisense RNA 1 (ZFAS1), a novel lncRNA transcribed in the antisense orientation of zinc finger NFX1-type containing 1(ZNFX1), was found to be increased in multiple cancers, such as gastric cancer and hepatocellular carcinoma, contributing to cancer development and progression. In the present review, we summarized recent progression on study of the functions and underlying molecular mechanisms of ZFAS1 related to occurrence and development of multiple cancers.