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Enzymes Dysregulation in Cancer: From Diagnosis to Therapeutical Approaches

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 16073

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Special Issue Editors

Prof. Dr. Valentina Pozzi

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Guest Editor

Department of Clinical Sciences, Polytechnic University of Marche, 60100 Ancona, Italy
Interests: Nicotinamide N-methyltransferase; Paraoxonase-2; biomarkers; cancer

Dr. Roberto Campagna

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Co-Guest Editor

Department of Clinical Sciences, Polytechnic University of Marche, 60100 Ancona, Italy
Interests: nicotinamide N-methyltransferase; paraoxonase-2; biomarkers; cancer
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Special Issue Information

Dear Colleagues,

Malignant transformation and cancer metabolism require important changes in enzymes expression and activity in order to support cell growth, invasion and metastasis. Furthermore, compared to normal cells, malignant cells are known to display dysregulated pathways to support cell functions in a microenvironment where there is a constant oxygen and nutrients restriction. Although on one hand these dysregulations boost the aggressive behavior of malignant cell, on the other hand they represent a potential therapeutical target for developing novel targeted therapies. For instance, in the last decades several inhibitors or monoclonal antibodies have been developed to specifically target dysregulated enzymes involved in tumor progression. Therefore, this special issue will be focused on discovering novel enzymatic pathways dysregulated in cancer, as well as identifying novel potential therapeutic targets for cancer management. Authors are invited to submit original researches, review articles, and short communications according to the topic of the special issue.

Prof. Dr. Valentina Pozzi
Dr. Roberto Campagna
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

biomarkers
cancer therapy
chemosensitivity
cell proliferation
metabolic enzyme

Published Papers (7 papers)

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Editorial

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3 pages, 185 KiB

Open AccessEditorial

Enzymes Dysregulation in Cancer: From Diagnosis to Therapeutical Approaches

by Valentina Pozzi, Roberto Campagna, Davide Sartini and Monica Emanuelli

Int. J. Mol. Sci. 2023, 24(18), 13815; https://doi.org/10.3390/ijms241813815 - 7 Sep 2023

Cited by 1 | Viewed by 728

Abstract

The metabolic reprogramming that occurs in cancer cells is a hallmark of cancer [...] Full article

(This article belongs to the Special Issue Enzymes Dysregulation in Cancer: From Diagnosis to Therapeutical Approaches)

Research

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8 pages, 282 KiB

Open AccessArticle

A Thermodynamic Approach to the Metaboloepigenetics of Cancer

by Umberto Lucia, Thomas S. Deisboeck, Antonio Ponzetto and Giulia Grisolia

Int. J. Mol. Sci. 2023, 24(4), 3337; https://doi.org/10.3390/ijms24043337 - 7 Feb 2023

Cited by 3 | Viewed by 1322

Abstract

We present a novel thermodynamic approach to the epigenomics of cancer metabolism. Here, any change in a cancer cell’s membrane electric potential is completely irreversible, and as such, cells must consume metabolites to reverse the potential whenever required to maintain cell activity, a process driven by ion fluxes. Moreover, the link between cell proliferation and the membrane’s electric potential is for the first time analytically proven using a thermodynamic approach, highlighting how its control is related to inflow and outflow of ions; consequently, a close interaction between environment and cell activity emerges. Lastly, we illustrate the concept by evaluating the Fe

^{2 +}

-flux in the presence of carcinogenesis-promoting mutations of the TET1/2/3 gene family. Full article

(This article belongs to the Special Issue Enzymes Dysregulation in Cancer: From Diagnosis to Therapeutical Approaches)

17 pages, 1517 KiB

Open AccessArticle

Combination Treatment of a Phytochemical and a Histone Demethylase Inhibitor—A Novel Approach towards Targeting TGFβ-Induced EMT, Invasion, and Migration in Prostate Cancer

by Nidhi Dalpatraj, Ankit Naik and Noopur Thakur

Int. J. Mol. Sci. 2023, 24(3), 1860; https://doi.org/10.3390/ijms24031860 - 17 Jan 2023

Cited by 5 | Viewed by 1925

Abstract

Minimizing side effects, overcoming cancer drug resistance, and preventing metastasis of cancer cells are of growing interest in current cancer therapeutics. Phytochemicals are being researched in depth as they are protective to normal cells and have fewer side effects. Hesperetin is a citrus bioflavonoid known to inhibit TGFβ-induced epithelial-to-mesenchymal transition (EMT), migration, and invasion of prostate cancer cells. Targeting epigenetic modifications that cause cancer is another class of upcoming therapeutics, as these changes are reversible. Global H3K27me3 levels have been found to be reduced in invasive prostate adenocarcinomas. Combining a demethylase inhibitor and a known anti-cancer phytochemical is a unique approach to targeting cancer to attain the aforementioned objectives. In the current study, we used an H3K27 demethylase (JMJD3/KDM6B) inhibitor to study its effects on TGFβ-induced EMT in prostate cancer cells. We then gave a combined hesperetin and GSK-J4 treatment to the PC-3 and LNCaP cells. There was a dose-dependent increase in cytotoxicity and inhibition of TGFβ-induced migration and invasion of prostate cancer cells after GSK-J4 treatment. GSK-J4 not only induced trimethylation of H3K27 but also induced the trimethylation of H3K4. Surprisingly, there was a reduction in the H3K9me3 levels. GSK-J4 alone and a combination of hesperetin and GSK-J4 treatment effectively inhibit the important hallmarks of cancer, such as cell proliferation, migration, and invasion, by altering the epigenetic landscape of cancer cells. Full article

(This article belongs to the Special Issue Enzymes Dysregulation in Cancer: From Diagnosis to Therapeutical Approaches)

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18 pages, 3087 KiB

Open AccessArticle

Expression and Function of StAR in Cancerous and Non-Cancerous Human and Mouse Breast Tissues: New Insights into Diagnosis and Treatment of Hormone-Sensitive Breast Cancer

by Pulak R. Manna, Sabarish Ramachandran, Jangampalli Adi Pradeepkiran, Deborah Molehin, Isabel Castro-Piedras, Kevin Pruitt, Vadivel Ganapathy and P. Hemachandra Reddy

Int. J. Mol. Sci. 2023, 24(1), 758; https://doi.org/10.3390/ijms24010758 - 1 Jan 2023

Cited by 4 | Viewed by 2174

Abstract

Breast cancer (BC) is primarily triggered by estrogens, especially 17β-estradiol (E2), which are synthesized by the aromatase enzyme. While all steroid hormones are derived from cholesterol, the rate-limiting step in steroid biosynthesis is mediated by the steroidogenic acute regulatory (StAR) protein. Herein, we demonstrate that StAR mRNA expression was aberrantly high in human hormone-dependent BC (MCF7, MDA-MB-361, and T-47D), modest in hormone-independent triple negative BC (TNBC; MDA-MB-468, BT-549, and MDA-MB-231), and had little to none in non-cancerous mammary epithelial (HMEC, MCF10A, and MCF12F) cells. In contrast, these cell lines showed abundant expression of aromatase (CYP19A1) mRNA. Immunofluorescence displayed qualitatively similar patterns of both StAR and aromatase expression in various breast cells. Additionally, three different transgenic (Tg) mouse models of spontaneous breast tumors, i.e., MMTV-Neu, MMTV-HRAS, and MMTV-PyMT, demonstrated markedly higher expression of StAR mRNA/protein in breast tumors than in normal mammary tissue. While breast tumors in these mouse models exhibited higher expression of ERα, ERβ, and PR mRNAs, their levels were undetected in TNBC tumors. Accumulation of E2 in plasma and breast tissues, from MMTV-PyMT and non-cancerous Tg mice, correlated with StAR, but not with aromatase, signifying the importance of StAR in governing E2 biosynthesis in mammary tissue. Treatment with a variety of histone deacetylase inhibitors (HDACIs) in primary cultures of enriched breast tumor epithelial cells, from MMTV-PyMT mice, resulted in suppression of StAR and E2 levels. Importantly, inhibition of StAR, concomitant with E2 synthesis, by various HDACIs, at clinical and preclinical doses, in MCF7 cells, indicated therapeutic relevance of StAR in hormone-dependent BCs. These findings provide insights into the molecular events underlying the differential expression of StAR in human and mouse cancerous and non-cancerous breast cells/tissues, highlighting StAR could serve not only as a novel diagnostic maker but also as a therapeutic target for the most prevalent hormone-sensitive BCs. Full article

(This article belongs to the Special Issue Enzymes Dysregulation in Cancer: From Diagnosis to Therapeutical Approaches)

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Review

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14 pages, 1504 KiB

Open AccessReview

The Role of NQO1 in Ovarian Cancer

by Giovanni Tossetta, Sonia Fantone, Gaia Goteri, Stefano Raffaele Giannubilo, Andrea Ciavattini and Daniela Marzioni

Int. J. Mol. Sci. 2023, 24(9), 7839; https://doi.org/10.3390/ijms24097839 - 25 Apr 2023

Cited by 29 | Viewed by 2327

Abstract

Ovarian cancer is one of the most dangerous gynecologic malignancies showing a high fatality rate because of late diagnosis and relapse occurrence due to chemoresistance onset. Several researchers reported that oxidative stress plays a key role in ovarian cancer occurrence, growth and development. The NAD(P)H:quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme that, using NADH or NADPH as substrates to reduce quinones to hydroquinones, avoids the formation of the highly reactive semiquinones, then protecting cells against oxidative stress. In this review, we report evidence from the literature describing the effect of NQO1 on ovarian cancer onset and progression. Full article

(This article belongs to the Special Issue Enzymes Dysregulation in Cancer: From Diagnosis to Therapeutical Approaches)

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14 pages, 6217 KiB

Open AccessReview

Prospects for Anti-Tumor Mechanism and Potential Clinical Application Based on Glutathione Peroxidase 4 Mediated Ferroptosis

by Mingliang Chen, Zhihao Shi, Yuqiu Sun, Haoran Ning, Xinyu Gu and Lei Zhang

Int. J. Mol. Sci. 2023, 24(2), 1607; https://doi.org/10.3390/ijms24021607 - 13 Jan 2023

Cited by 13 | Viewed by 3972

Abstract

Ferroptosis, characterized by excessive iron accumulation and lipid peroxidation, is a novel form of iron-dependent cell death, which is morphologically, genetically, and biochemically distinct from other known cell death types, such as apoptosis, necrosis, and autophagy. Emerging evidence shows that glutathione peroxidase 4 (GPX4), a critical core regulator of ferroptosis, plays an essential role in protecting cells from ferroptosis by removing the product of iron-dependent lipid peroxidation. The fast-growing studies on ferroptosis in cancer have boosted a perspective on its use in cancer therapeutics. In addition, significant progress has been made in researching and developing tumor therapeutic drugs targeting GPX4 based on ferroptosis, especially in acquired drug resistance. Selenium modulates GPX4-mediated ferroptosis, and its existing form, selenocysteine (Sec), is the active center of GPX4. This review explored the structure and function of GPX4, with the overarching goal of revealing its mechanism and potential application in tumor therapy through regulating ferroptosis. A deeper understanding of the mechanism and application of GPX4-mediated ferroptosis in cancer therapy will provide new strategies for the research and development of antitumor drugs. Full article

(This article belongs to the Special Issue Enzymes Dysregulation in Cancer: From Diagnosis to Therapeutical Approaches)

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15 pages, 1162 KiB

Open AccessReview

Metformin Improves Ovarian Cancer Sensitivity to Paclitaxel and Platinum-Based Drugs: A Review of In Vitro Findings

by Giovanni Tossetta

Int. J. Mol. Sci. 2022, 23(21), 12893; https://doi.org/10.3390/ijms232112893 - 25 Oct 2022

Cited by 42 | Viewed by 2881

Abstract

Ovarian cancer is one of the most dangerous gynecologic cancers worldwide, showing a high fatality rate and recurrence due to diagnosis at an advanced stage of the disease and the occurrence of chemoresistance, which weakens the therapeutic effects of the chemotherapeutic treatments. In fact, although paclitaxel and platinum-based drugs (carboplatin or cisplatin) are widely used alone or in combination to treat ovarian cancer, the occurrence of chemoresistance significantly reduces the effects of these drugs. Metformin is a hypoglycemic agent that is commonly used for the treatment of type 2 diabetes mellitus and non-alcoholic fatty liver disease. However, this drug also shows anti-tumor activity, reducing cancer risk and chemoresistance. This review analyzes the current literature regarding the role of metformin in ovarian cancer and investigates what is currently known about its effects in reducing paclitaxel and platinum resistance to restore sensitivity to these drugs. Full article

(This article belongs to the Special Issue Enzymes Dysregulation in Cancer: From Diagnosis to Therapeutical Approaches)

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