Molecular Biology

Oncotarget

Oncotarget published "Reversing oncogenic transformation with iron chelation" which reported that cancer cells accumulate iron to supplement their aberrant growth and metabolism.

Depleting cells of iron by iron chelators has been shown to be selectively cytotoxic to cancer cells in vitro and in vivo. A plethora of studies have shown iron chelators can reverse some of the major hallmarks and enabling characteristics of cancer. Iron chelators inhibit signalling pathways that drive proliferation, migration and metastasis as well as return tumour suppressive signalling. Iron chelators target cancer cell metabolism, attenuating oxidative phosphorylation and glycolysis.

Dr. Gina Abdelaal from The Northumbria University said, "Iron is vital for normal cell growth and survival."

Cancer is an evolutionary maverick, which exploits its trademark genomic instability to drain environmental resources. As an enzyme cofactor, iron is responsible for many cellular processes including mitochondrial metabolism and DNA synthesis. As iron can drive cellular proliferation, cancer cells have an adapted iron metabolism allowing increased iron accumulation. The thiosemicarbazone class is a later stage of iron chelator evolution which manifested in 1992.

Unlike their predecessor DFO, thiosemicarbazone chelators are capable of inducing reactive oxygen species. Triapine is a thiosemicarbazone; its primary mode of action is thought to be ribonucleotide reductase inhibition with a higher potency than commonly used ribonucleotide reductase inhibitor, hydroxyurea. This approach is predicted to protect healthy tissues from the cytotoxic effects as the timing and place of the drug release can be controlled.

Encapsulating Dp44mT in PLGA nanoparticles enhanced its ability to induce apoptosis and improved its selectivity towards cancer cells.

At present many more classes of iron chelators are being taken into consideration as potential cancer therapy candidates.

The Abdelaal Research Team concluded in their Oncotarget Research Output that based on the data presented in this review iron chelators could potentially reverse many of the key hallmarks of cancer. Stripping the cells of iron impacts many cellular targets with some targets still undiscovered. NDRG1 has been proven to be the common link between the ability of iron chelators to reverse many of the hallmarks of cancer as overexpression of NDRG1 mimics the impact of iron chelation on several signalling pathways. There are still many unanswered questions about the mechanism of action of iron chelators.

A consensus must be reached on the impact of iron chelation on angiogenesis through in vivo studies. As STAT3 is essential for VEGF gene expression and iron chelation attenuates STAT3 dimerisation and nuclear localisation. The cleaved isoform is only present in cancer cells and could potentially be oncogenic. Although many mechanistic studies have been undertaken iron chelators, the complexity of cell signalling remains a hurdle preventing the discovery of all cellular targets of iron chelation. A potential way of discovering new targets is combining iron chelators with well-characterised cancer therapeutics.

DOI - https://doi.org/10.18632/oncotarget.27866

Full text - https://www.oncotarget.com/article/27866/text/

Correspondence to - Gina Abdelaal - gina.abdelaal@northumbria.ac.uk

Keywords - iron chelator, oncogenesis, selective cytotoxicity, hallmarks of cancer, NDRG1

About Oncotarget

Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls

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Author Testimonial: Dr. Gina Abdelaal - Northumbria University

Author Insight: Reversing Oncogenic Transformation With Iron Chelation

Teach Me in 10

In some patients, the rapid antidepressant action of ketamine can last for days, or even weeks. This, says Dr. Lisa Monteggia, is incredible for a drug that is cleared from the body very quickly. Over recent years, The Monteggia laboratory at the University of Vanderbilt has been investigating the molecular mechanisms that underly this rapid action.  In this Teach Me in 10, Dr. Monteggia outlines some of the key discoveries that her team have made, particularly in relation to ketamine, neuroplasticity and neuroreceptors.

Ketamine as an Antidepressant With Dr. Lisa Monteggia

The cover for issue 36 of Oncotarget features Figure 7, "Knockdown of APOBEC3B is associated with a lower tumor growth in an adrenocortical carcinoma xenograft mouse model," by Gara, et al. which reported that the role of APOBEC3B in adrenocortical carcinoma and the mechanisms through which its expression is regulated in cancer are not fully understood.

Here, the authors report that APOBEC3B is overexpressed in ACC and it regulates cell proliferation by inducing S phase arrest. They show high APOBEC3B expression is associated with a higher copy number gain/loss at chromosome 4 and 8 and TP53 mutation rate in ACC.

GATA3 was identified as a positive regulator of APOBEC3B expression and directly binds the APOBEC3B promoter region.

Both GATA3 and APOBEC3B expression levels were associated with patient survival.

This Oncotarget study provides novel insights into the function and regulation of APOBEC3B expression in addition to its known mutagenic ability.

Dr. Electron Kebebew from Stanford University said, "Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy."

The distinct pattern of DNA base alterations has been characterized in the cancer genome using high throughput deep sequencing technologies, that reflect the underlying mutational process.

Whole-genome and exome mutation analysis of The Cancer Genome Atlas data on multiple cancers has revealed that this pattern is consistent with the deaminase activity of the AID/APOBEC family of enzymes, therefore, implying its significance as an endogenous mutator and a crucial contributor to somatic mutations and genomic instability.

APOBEC3B is overexpressed in ovarian cancer cell lines and high-grade primary ovarian cancers.

In addition, APOBEC3B expression is positively correlated with the total mutation load, as well as, elevated levels of transversion mutations.

Given there are no well-established exogenous factors associated with ACC, the Oncotarget authors postulated whether APOBEC3B could be an endogenous mechanism of genomic instability/mutations in ACC and investigated its function in vitro and in vivo.

The Kebebew Research Team concluded in their Oncotarget Research Paper, "APOBEC3B overexpressed in ACC, and is associated with DNA damage, S phase arrest, higher copy number alterations and TP53 mutations in ACC. For the first time, we demonstrated that GATA3 directly regulates the expression of APOBEC3B and that both are prognostic markers in ACC."

DOI - https://doi.org/10.18632/oncotarget.27703

Full text - https://www.oncotarget.com/article/27703/text/

Correspondence to - Electron Kebebew - kebebew@stanford.edu

Keywords - adrenocortical carcinoma, APOBEC3B, GATA3, prognosis, DNA damage

About Oncotarget

Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. 

To learn more about Oncotarget, please visit https://www.oncotarget.com/ or connect with:

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Oncotarget is published by Impact Journals, LLC. Please visit https://www.impactjournals.com/ or connect with @ImpactJrnls

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Author Testimonial: Dr. Monica Varun Tyagi - Stanford University

Aging (Aging-US)

For Aging’s Volume 11, Issue 18, the Journal devoted the Cover to a research paper by Dr. Alejandro Martin-Montalvo from the Department of Regeneration and Cell Therapy, Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Sevilla, Spain

Herein, the authors show, using wild-type and the Pax8 ablated model of hypothyroidism in mice, that hyperthyroidism and severe hypothyroidism are associated with an overall unhealthy status and shorter lifespan.

Mild hypothyroid Pax8 +/- mice were heavier and displayed insulin resistance, hepatic steatosis and increased prevalence of liver cancer yet had normal lifespan.

Dr. Martin-Montalvo said, "The increasing burden of age-related diseases highlights the importance of uncovering the mechanisms underlying the aging process."

TSH stimulates the production of T4 and T3 in the thyroid gland, which in turn inhibit both TRH and TSH synthesis when THs reach the hypothalamus and hypophysis, respectively.

Greater life expectancy has been associated with reduced circulating levels of T4, T3, and/or high TSH levels in both animal models and humans.

In this line, the Laron, Ames and Snell dwarf mice, which have reduced GH signalling and reduced circulating TH levels, exhibit a consistent exceptional lifespan as well as other metabolic alterations such as enhanced hepatic insulin sensitivity.

Both rodents and humans under calorie restriction, which comprises a variety of nutritional interventions with several beneficial effects including extended longevity, exhibit reduced circulating T3 levels and/or high TSH levels.

Likewise, nonagenarians from families with exceptional long lifespans, as well as their descendants, have been reported to exhibit increased TSH levels and/or decreased circulating T3 levels.

The Martin-Montalvo research team concluded, "In 1908 Dr. Max Rubner proposed the rate of living theory of aging and longevity, postulating that species with a low metabolic rate would have increased life expectancy when compared to species with a higher metabolic rate.

In this line, restricted levels of THs, which control the metabolic rate, have been associated with increased longevity as well as metabolic fitness."

Full Text - https://www.aging-us.com/article/102285/text

Correspondence to: Alejandro Martin-Montalvo; email: alejandro.martinmontalvo@cabimer.es and Benoit Raymond Gauthier; email: benoit.gauthier@cabimer.es

Keywords: lifespan, healthspan, thyroid hormones, hyperthyroidism, hypothyroidism, glucose metabolism

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways.

Please visit our website at http://www.Aging-US.com or connect with us on:

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Facebook - https://www.facebook.com/AgingUS/
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Aging-US is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls

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Author Insight: Imbalanced Thyroid Hormones Sensitize to Hepatocarcinogenesis, Unhealthy Aging

Aging-US published a Special Collection on Eye Disease which included "Age-related changes in eye lens biomechanics, morphology, refractive index and transparency" which reported that life-long eye lens function requires an appropriate gradient refractive index, biomechanical integrity and transparency.

The authors conducted an extensive study of wild-type mouse lenses 1-30 months of age to define common age-related changes. Biomechanical testing and morphometrics revealed an increase in lens volume and stiffness with age. Their results suggest similarities between murine and primate lenses and provide a baseline for future lens aging studies.

Dr. Velia M. Fowler and Dr. Catherine Cheng said, "The eye lens is required for fine focusing of light onto the retina to form a clear image, and the function of the lens is intimately tied to its shape, biomechanical properties, transparency and refractive index."

The eye lens is required for fine focusing of light onto the retina to form a clear image. It has long been known that age-related changes in these lens properties lead to two major lens pathologies, cataracts and presbyopia. Presbyopia is caused by a reduction in the lens' ability to change shape during focusing (accommodation), and, by extension, the need for reading glasses. Mice offer an opportunity to investigate changes in lens morphometrics, stiffness, transparency and refractive properties with age in a relatively shortened period of time. Little is known about the morphological, mechanical, refractive and cellular changes that occur with advanced age in the lens. The authors demonstrate that age-related changes in mouse lenses mimic some aspects of aging in human lenses.

The Fowler/Cheng Research Team concluded in their Aging-US Research Output, "the increases in lens size and nucleus size are correlated with increase stiffness with age. The addition of new fiber cells at the lens periphery becomes disordered with age, but this does not appear to impact lens biomechanical properties. Cataracts in aged lenses can be due to cell structural abnormalities, including incomplete suture closure, collapse of the lens epithelial cell layer into the suture gap and loss of epithelial-fiber cell attachments and compaction of the cortical lens fiber cells forming a circumferential light scattering ring. GRIN is present in the lens from 2 weeks of age and continues to increase until about 6 months of age, after which the maximum refractive index remains stable. The increase in the area of highest refractive index at the center of the lens is directly correlated with the increase in lens nucleus size, suggesting nuclear compaction drives the maximum GRIN. Whether there is a common molecular mechanism that drives changes in all the measured parameters remains unknown, but further biochemical and cell morphology studies will be needed to determine how subcellular aging affects the whole tissue. Thus, our study provides a baseline for future studies of lens aging by providing quantitative measurements of key parameters and identifying common age-related changes in the overall tissue and in individual cells"

Full Text - https://www.aging-us.com/article/102584/text

Correspondence to: Velia M. Fowler email: vfowler@udel.edu and Catherine Cheng email: ckcheng@iu.edu

Keywords: fiber cell, strain, epithelial cell, cataract, stiffness

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

Please visit our website at http://www.Aging-US.com​​ or connect with us on:

SoundCloud - https://soundcloud.com/Aging-Us
Facebook - https://www.facebook.com/AgingUS/
Twitter - https://twitter.com/AgingJrnl
Instagram - https://www.instagram.com/agingjrnl/
YouTube - https://www.youtube.com/agingus​
LinkedIn - https://www.linkedin.com/company/aging/
Pinterest - https://www.pinterest.com/AgingUS/

Aging-US is published by Impact Journals, LLC please visit http://www.ImpactJournals.com​​ or connect with @ImpactJrnls

Media Contact
18009220957
MEDIA@IMPACTJOURNALS.COM

Author Insight: Age-related Changes in Eye Lens Biomechanics

The cover for issue 36 of Oncotarget features Figure 7, "Knockdown of APOBEC3B is associated with a lower tumor growth in an adrenocortical carcinoma xenograft mouse model," by Gara, et al. which reported that the role of APOBEC3B in adrenocortical carcinoma and the mechanisms through which its expression is regulated in cancer are not fully understood.

Here, the authors report that APOBEC3B is overexpressed in ACC and it regulates cell proliferation by inducing S phase arrest. They show high APOBEC3B expression is associated with a higher copy number gain/loss at chromosome 4 and 8 and TP53 mutation rate in ACC.

GATA3 was identified as a positive regulator of APOBEC3B expression and directly binds the APOBEC3B promoter region.

Both GATA3 and APOBEC3B expression levels were associated with patient survival.

This Oncotarget study provides novel insights into the function and regulation of APOBEC3B expression in addition to its known mutagenic ability.

Dr. Electron Kebebew from Stanford University said, "Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy."

The distinct pattern of DNA base alterations has been characterized in the cancer genome using high throughput deep sequencing technologies, that reflect the underlying mutational process.

Whole-genome and exome mutation analysis of The Cancer Genome Atlas data on multiple cancers has revealed that this pattern is consistent with the deaminase activity of the AID/APOBEC family of enzymes, therefore, implying its significance as an endogenous mutator and a crucial contributor to somatic mutations and genomic instability.

APOBEC3B is overexpressed in ovarian cancer cell lines and high-grade primary ovarian cancers.

In addition, APOBEC3B expression is positively correlated with the total mutation load, as well as, elevated levels of transversion mutations.

Given there are no well-established exogenous factors associated with ACC, the Oncotarget authors postulated whether APOBEC3B could be an endogenous mechanism of genomic instability/mutations in ACC and investigated its function in vitro and in vivo.

The Kebebew Research Team concluded in their Oncotarget Research Paper, "APOBEC3B overexpressed in ACC, and is associated with DNA damage, S phase arrest, higher copy number alterations and TP53 mutations in ACC. For the first time, we demonstrated that GATA3 directly regulates the expression of APOBEC3B and that both are prognostic markers in ACC."

DOI - https://doi.org/10.18632/oncotarget.27703

Full text - https://www.oncotarget.com/article/27703/text/

Correspondence to - Electron Kebebew - kebebew@stanford.edu

Keywords - adrenocortical carcinoma, APOBEC3B, GATA3, prognosis, DNA damage

About Oncotarget

Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with:

SoundCloud - https://soundcloud.com/oncotarget
Facebook - https://www.facebook.com/Oncotarget/
Twitter - https://twitter.com/oncotarget
Instagram - https://www.instagram.com/oncotargetj...
YouTube - https://www.youtube.com/c/OncotargetY...
LinkedIn - https://www.linkedin.com/company/onco...
Pinterest - https://www.pinterest.com/oncotarget/
Reddit - https://www.reddit.com/user/Oncotarget/

Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls

Media Contact
MEDIA@IMPACTJOURNALS.COM
18009220957

Author Insight: GATA3 and APOBEC3B are Prognostic Markers in Adrenocortical Carcinoma

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