bims-kracam 2021-09-05 papers

on K-Ras in cancer metabolism

Issue of 2021–09–05
nineteen papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development

Current advances and trends in KRAS targeted therapies for colorectal cancer.
The KRAS-G12C inhibitor: activity and resistance.
Regulation of antitumor immunity by inflammation-induced epigenetic alterations.
Potassium and Sodium Channels and the Warburg Effect: Biophysical Regulation of Cancer Metabolism.
Camalexin, an indole phytoalexin, inhibits cell proliferation, migration, and mammosphere formation in breast cancer cells via the aryl hydrocarbon receptor.
Cysteine Boosts Fitness Under Hypoxia-Mimicked Conditions in Ovarian Cancer by Metabolic Reprogramming.
Targeting of cancer cell death mechanisms by curcumin; implications to cancer therapy.
Polyamine homeostasis-based strategies for cancer: The role of combination regimens.
Evaluation of Impacts of Cellular Metabolism on the Migration of Ovarian Cancer Cells by Two in Vitro Assays: A Method Comparison Study.
The Multifaceted Roles of Proline in Cell Behavior.
Roles of Mitochondrial Serine Hydroxymethyltransferase 2 (SHMT2) in Human Carcinogenesis.
Glutamine metabolism regulates endothelial to hematopoietic transition and hematopoietic lineage specification.
The context-specific roles of urea cycle enzymes in tumorigenesis.
Patient-Derived Xenografts to Study Cancer Metabolism: When Does X Mark the Spot?
Metabolism-associated genes in occurrence and development of gastrointestinal cancer: Latest progress and future prospect.
Atorvastatin facilitates chemotherapy effects in metastatic triple-negative breast cancer.
Organelle-specific regulation of ferroptosis.
Endogenous estrogens-breast cancer and chemoprevention.
Nanoparticle-Mediated Inhibition of Mitochondrial Glutaminolysis to Amplify Oxidative Stress for Combination Cancer Therapy.

Mol Cancer Res. 2021 Aug 30. pii: molcanres.0248.2021. [Epub ahead of print]

Current advances and trends in KRAS targeted therapies for colorectal cancer.

M Y M Teo, J Y Fong, W M Lim, L L A In.

KRAS gene somatic point mutations is one of the most prominently mutated proto-oncogenes known to date, and accounts for approximately 60% of all colorectal cancer cases. One of the most exciting drug development areas against colorectal cancer is the targeting of undruggable kinases and kinase-substrate molecules, although whether and how they can be integrated with other therapies remains a question. Current clinical trial data have provided supporting evidence on the use of combination treatment involving MEK inhibitors and either one of the PI3K inhibitors for metastatic colorectal cancer patients to avoid the development of resistance and provide effective therapeutic outcome rather than using a single agent alone. Many clinical trials are also ongoing to evaluate different combinations of these pathway inhibitors in combination with immunotherapy for colorectal cancer patients whose current palliative treatment options are limited. Nevertheless, continued assessment of these targeted cancer therapies will eventually allow colorectal cancer patients to be treated using a personalized medicine approach. In this review, the most recent scientific approaches and clinical trials targeting KRAS mutations directly or indirectly for the management of colorectal cancer are discussed.

DOI: https://doi.org/10.1158/1541-7786.MCR-21-0248
Cancer Gene Ther. 2021 Sep 01.

The KRAS-G12C inhibitor: activity and resistance.

Jiao Liu, Rui Kang, Daolin Tang.

Although it has long been deemed "undruggable", with the development of drugs specifically binding the KRAS-G12C mutant protein, clinical trials that directly inhibit oncogenic RAS have recently made promising improvements. In particular, the covalent KRAS-G12C inhibitors sotorasib and adagrasib are used to treat patients with advanced non-small cell lung cancer (NSCLC) carrying KRAS-G12C mutations. Unfortunately, the vast majority of patients do not respond to KRAS-G12C inhibitor therapy, mainly due to intrinsic or acquired resistance caused by cellular, molecular, and genetic mechanisms. Improving the understanding of drug response in the tumor microenvironment may continue to promote the design, testing, and clinical application of KRAS-G12C inhibitors.

DOI: https://doi.org/10.1038/s41417-021-00383-9
Cell Mol Immunol. 2021 Aug 31.

Regulation of antitumor immunity by inflammation-induced epigenetic alterations.

Michael Karin, Shabnam Shalapour.

  Chronic inflammation promotes tumor development, progression, and metastatic dissemination and causes treatment resistance. The accumulation of genetic alterations and loss of normal cellular regulatory processes are not only associated with cancer growth and progression but also result in the expression of tumor-specific and tumor-associated antigens that may activate antitumor immunity. This antagonism between inflammation and immunity and the ability of cancer cells to avoid immune detection affect the course of cancer development and treatment outcomes. While inflammation, particularly acute inflammation, supports T-cell priming, activation, and infiltration into infected tissues, chronic inflammation is mostly immunosuppressive. However, the main mechanisms that dictate the outcome of the inflammation-immunity interplay are not well understood. Recent data suggest that inflammation triggers epigenetic alterations in cancer cells and components of the tumor microenvironment. These alterations can affect and modulate numerous aspects of cancer development, including tumor growth, the metabolic state, metastatic spread, immune escape, and immunosuppressive or immunosupportive leukocyte generation. In this review, we discuss the role of inflammation in initiating epigenetic alterations in immune cells, cancer-associated fibroblasts, and cancer cells and suggest how and when epigenetic interventions can be combined with immunotherapies to improve therapeutic outcomes.

Keywords:  Antitumor immunity; Epigenetics; Immunotherapy; Inflammation

DOI:  https://doi.org/10.1038/s41423-021-00756-y
Bioelectricity. 2019 Sep 01. 1(3): 188-200

Potassium and Sodium Channels and the Warburg Effect: Biophysical Regulation of Cancer Metabolism.

Jessica Iorio, Giulia Petroni, Claudia Duranti, Elena Lastraioli.

  Ion channels are progressively emerging as a novel class of membrane proteins expressed in several types of human cancers and regulating the different aspects of cancer cell behavior. The metabolism of cancer cells, usually composed by a variable proportion of respiration, glycolysis, and glutaminolysis, leads to the excessive production of acidic metabolic products. The presence of these acidic metabolites inside the cells results in intracellular acidosis, and hinders survival and proliferation. For this reason, tumor cells activate mechanisms of pH control that produce a constitutive increase in intracellular pH (pHi) that is more acidic than the extracellular pH (pHe). This condition forms a perfect microenvironment for metastatic progression and may be permissive for some of the acquired characteristics of tumors. Recent analyses have revealed complex interconnections between oncogenic activation, ion channels, hypoxia signaling and metabolic pathways that are dysregulated in cancer. Here, we summarize the molecular mechanisms of the Warburg effect and hypoxia and their association. Moreover, we discuss the recent findings concerning the involvement of ion channels in various aspects of the Warburg effect and hypoxia, focusing on the role of Na+ and K+ channels in hypoxic and metabolic reprogramming in cancer.

Keywords:  Warburg effect; cancer; ion channels

DOI:  https://doi.org/10.1089/bioe.2019.0017
J Nat Med. 2021 Aug 31.

Camalexin, an indole phytoalexin, inhibits cell proliferation, migration, and mammosphere formation in breast cancer cells via the aryl hydrocarbon receptor.

Naoya Yamashita, Chiharu Taga, Moeno Ozawa, Yuichiro Kanno, Noriko Sanada, Ryoichi Kizu.

  Breast cancer is the most commonly diagnosed cancer among women worldwide. Despite a variety of drugs available for the treatment of patients with breast cancer, drug resistance remains a significant clinical problem. Therefore, there is an urgent need to develop drugs with new mechanisms of action. Camalexin is the main indole phytoalexin in Arabidopsis thaliana and other crucifers. Camalexin inhibits the proliferation of various cancer cells. However, the mechanism by which camalexin inhibits cell proliferation remains unclear. In this study, we found that camalexin inhibited cell proliferation and migration of breast cancer cell lines. Furthermore, camalexin also suppressed breast cancer stem cell-derived mammosphere formation. We previously reported that the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) agonist suppresses mammosphere formation. Several compounds with indole structures are known to act as AhR agonists. Therefore, we hypothesized that the inhibition of mammosphere formation by camalexin may involve AhR activation. We found that camalexin increased the nuclear translocation of AhR, AhR-mediated transcriptional activation, and expression of AhR target genes. In addition, camalexin suppressed mammosphere formation in AhR-expressing breast cancer cells more than in the breast cancer cells that lacked AhR expression. Taken together, the data demonstrate that camalexin is a novel AhR agonist and that the inhibition of cell proliferation, migration, and mammosphere formation by camalexin involves the activation of AhR. Our findings suggest that camalexin, an AhR agonist, may be a novel therapeutic agent for breast cancer.

Keywords:  Aryl hydrocarbon receptor; Breast cancer stem cell; Camalexin; Mammosphere; Phytoalexin

DOI:  https://doi.org/10.1007/s11418-021-01560-8
Front Cell Dev Biol. 2021 ;9 722412

Cysteine Boosts Fitness Under Hypoxia-Mimicked Conditions in Ovarian Cancer by Metabolic Reprogramming.

Sofia C Nunes, Cristiano Ramos, Inês Santos, Cindy Mendes, Fernanda Silva, João B Vicente, Sofia A Pereira, Ana Félix, Luís G Gonçalves, Jacinta Serpa.

  Among gynecologic malignancies, ovarian cancer is the third most prevalent and the most common cause of death, especially due to diagnosis at an advanced stage together with resistance to therapy. As a solid tumor grows, cancer cells in the microenvironment are exposed to regions of hypoxia, a selective pressure prompting tumor progression and chemoresistance. We have previously shown that cysteine contributes to the adaptation to this hypoxic microenvironment, but the mechanisms by which cysteine protects ovarian cancer cells from hypoxia-induced death are still to be unveiled. Herein, we hypothesized that cysteine contribution relies on cellular metabolism reprogramming and energy production, being cysteine itself a metabolic source. Our results strongly supported a role of xCT symporter in energy production that requires cysteine metabolism instead of hydrogen sulfide (H2S) per se. Cysteine degradation depends on the action of the H2S-synthesizing enzymes cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and/or 3-mercaptopyruvate sulfurtransferase (MpST; together with cysteine aminotransferase, CAT). In normoxia, CBS and CSE inhibition had a mild impact on cysteine-sustained ATP production, pointing out the relevance of CAT + MpST pathway. However, in hypoxia, the concomitant inhibition of CBS and CSE had a stronger impact on ATP synthesis, thus also supporting a role of their hydrogen sulfide and/or cysteine persulfide-synthesizing activity in this stressful condition. However, the relative contributions of each of these enzymes (CBS/CSE/MpST) on cysteine-derived ATP synthesis under hypoxia remains unclear, due to the lack of specific inhibitors. Strikingly, NMR analysis strongly supported a role of cysteine in the whole cellular metabolism rewiring under hypoxia. Additionally, the use of cysteine to supply biosynthesis and bioenergetics was reinforced, bringing cysteine to the plateau of a main carbon sources in cancer. Collectively, this work supports that sulfur and carbon metabolism reprogramming underlies the adaptation to hypoxic microenvironment promoted by cysteine in ovarian cancer.

Keywords:  bioenergetics; carbon source; cysteine; cystine; hydrogen sulfide; hypoxia; microenvironment; ovarian cancer

DOI:  https://doi.org/10.3389/fcell.2021.722412
Basic Clin Pharmacol Toxicol. 2021 Sep 02.

Targeting of cancer cell death mechanisms by curcumin; implications to cancer therapy.

Chong Yu, Bo Yang, Masoud Najafi.

  Cancer is known as a second major cause of death globally. Nowadays, several modalities have been developed for the treatment of cancer. Radiotherapy and chemotherapy are the most common modalities in most countries. However, newer modalities such as immunotherapy and targeted therapy drugs can kill cancer cells with minimal side effects. All anti-cancer agents work based on the killing of cancer cells. Numerous studies are ongoing to kill cancer cells more effectively without increasing side effects to normal tissues. The combination modalities with low toxic agents are interesting for this aim. Curcumin is one of the most common herbal agents that has shown several anti-cancer properties. It can regulate immune system responses against cancer. Furthermore, curcumin has been shown to potentiate cell death signalling pathways and attenuate survival signalling pathways in cancer cells. The knowledge of how curcumin induces cell death in cancers can improve therapeutic efficiency. In this review, the regulatory effects of curcumin on different cell death mechanisms and their signalling pathways will be discussed. Furthermore, we explain how curcumin may potentiate the anti-cancer effects of other drugs or radiotherapy through modulation of apoptosis, mitotic catastrophe, senescence, autophagy, and ferroptosis.

Keywords:  Cancer; Cell death; Chemotherapy; Curcumin; Radiotherapy

DOI:  https://doi.org/10.1111/bcpt.13648
Eur J Pharmacol. 2021 Aug 28. pii: S0014-2999(21)00610-5. [Epub ahead of print] 174456

Polyamine homeostasis-based strategies for cancer: The role of combination regimens.

Qi-Zhang Li, Zan-Wen Zuo, Ze-Rong Zhou, Yan Ji.

  Spermine, spermidine and putrescine polyamines are naturally occurring ubiquitous positively charged amines and are essential metabolites for biological functions in our life. These compounds play a crucial role in many cell processes, including cellular proliferation, growth, and differentiation. Intracellular levels of polyamines depend on their biosynthesis, transport and degradation. Polyamine levels are high in cancer cells, which leads to the promotion of tumor growth, invasion and metastasis. Targeting polyamine metabolism as an anticancer strategy is considerably rational. Due to compensatory mechanisms, a single strategy does not achieve satisfactory clinical effects when using a single agent. Combination regimens are more clinically promising for cancer chemoprevention because they work synergistically with causing little or no adverse effects due to each individual agent being used at lower doses. Moreover, bioactive substances have advantages over single chemical agents because they can affect multiple targets. In this review, we discuss anticancer strategies targeting polyamine metabolism and describe how combination treatments and effective natural active ingredients are promising therapies. The existing research suggests that polyamine metabolic enzymes are important therapeutic targets and that combination therapies can be more effective than monotherapies based on polyamine depletion.

Keywords:  Antitumor; Combination; Natural products; Polyamine metabolism; Small molecules

DOI:  https://doi.org/10.1016/j.ejphar.2021.174456
Galen Med J. 2020 ;9 e1831

Evaluation of Impacts of Cellular Metabolism on the Migration of Ovarian Cancer Cells by Two in Vitro Assays: A Method Comparison Study.

Hossein Ghahremani, Majid Sirati-Sabet, Siamak Salami.

   Background: Alteration of metabolic pathways in cancer cells can intensely modulate their migration as an important step in invasion and metastasis. Ketogenic diet showed some contradictory results in cancer patients. In this study the impact of metabolic reprogramming of A2780CP as a model of ovarian cancer stem-like cells on cell migration by two in vitro methods: wound healing and soft agar colony-forming assays.
Materials and Methods: short term and long term metabolic reprogramming were done by restriction of glucose to 250mg/L with or without enrichment with beta-hydroxybutyrate (5 milimolar) for 48 hours and 30 days, respectively. Wound healing assay was done and the wound ratio was calculated for 24 and 48 hours. Soft agar colony formation assay was also done in treated and control cells. For method comparison, ten biological replicates were analyzed in triplicate.
Results: Migration of A2780CP ovarian cancer stem-like cells were significantly alleviated by long term glucose restriction but no significant changes were observed in short term study. Beta-hydroxybutyrate enrichment did not produce significant impacts on glucose restriction in short or long term studies.
Conclusion: The results of colony formation in soft agar and wound or scratch healing assay were in good correlation and convergence which could be used interchangeably in the investigation of metabolic reprogramming in cancer cells.

Keywords:  Cell Migration; In Vitro Techniques; Metabolism; Neoplastic Stem Cells; Ovarian Neoplasms

DOI:  https://doi.org/10.31661/gmj.v9i0.1831
Front Cell Dev Biol. 2021 ;9 728576

The Multifaceted Roles of Proline in Cell Behavior.

Eduardo J Patriarca, Federica Cermola, Cristina D'Aniello, Annalisa Fico, Ombretta Guardiola, Dario De Cesare, Gabriella Minchiotti.

  Herein, we review the multifaceted roles of proline in cell biology. This peculiar cyclic imino acid is: (i) A main precursor of extracellular collagens (the most abundant human proteins), antimicrobial peptides (involved in innate immunity), salivary proteins (astringency, teeth health) and cornifins (skin permeability); (ii) an energy source for pathogenic bacteria, protozoan parasites, and metastatic cancer cells, which engage in extracellular-protein degradation to invade their host; (iii) an antistress molecule (an osmolyte and chemical chaperone) helpful against various potential harms (UV radiation, drought/salinity, heavy metals, reactive oxygen species); (iv) a neural metabotoxin associated with schizophrenia; (v) a modulator of cell signaling pathways such as the amino acid stress response and extracellular signal-related kinase pathway; (vi) an epigenetic modifier able to promote DNA and histone hypermethylation; (vii) an inducer of proliferation of stem and tumor cells; and (viii) a modulator of cell morphology and migration/invasiveness. We highlight how proline metabolism impacts beneficial tissue regeneration, but also contributes to the progression of devastating pathologies such as fibrosis and metastatic cancer.

Keywords:  antistress activity; cell plasticity; energy source; extracellular proteins; metabolism; neural toxicity; proline metabolism; signaling modulators

DOI:  https://doi.org/10.3389/fcell.2021.728576
J Cancer. 2021 ;12(19): 5888-5894

Roles of Mitochondrial Serine Hydroxymethyltransferase 2 (SHMT2) in Human Carcinogenesis.

Yuanyuan Zeng, Jie Zhang, Mengmeng Xu, Fuxian Chen, Ruidong Zi, Jicheng Yue, Yanan Zhang, Nannan Chen, Y Eugene Chin.

  In the last few years, cellular metabolic reprogramming has been acknowledged as a hallmark of human cancer and evaluated for its crucial role in supporting the proliferation and survival of human cancer cells. In a variety of human tumours, including hepatocellular carcinoma (HCC), breast cancer and non-small-cell lung cancer (NSCLC), a large amount of carbon is reused in serine/glycine biosynthesis, accompanied by higher expression of the key glycine synthetic enzyme mitochondrial serine hydroxymethyltransferase 2 (SHMT2). This enzyme can convert serine into glycine and a tetrahydrofolate-bound one-carbon unit, ultimately supporting thymidine synthesis and purine synthesis and promoting tumour growth. In tumour samples, elevated expression of SHMT2 was found to be associated with poor prognosis. In this review, the pivotal roles of SHMT2 in human carcinogenesis are described, highlighting the underlying regulatory mechanisms through promotion of tumour progression. In conclusion, SHMT2 may serve as a prognostic marker and a target for anticancer therapies.

Keywords:  Serine hydroxymethyltransferase 2 (SHMT2); cell proliferation; human carcinogenesis; predictive biomarker; tumour growth

DOI:  https://doi.org/10.7150/jca.60170
Sci Rep. 2021 Sep 02. 11(1): 17589

Glutamine metabolism regulates endothelial to hematopoietic transition and hematopoietic lineage specification.

Leal Oburoglu, Els Mansell, Niels-Bjarne Woods.

During hematopoietic development, definitive hematopoietic cells are derived from hemogenic endothelial (HE) cells through a process known as endothelial to hematopoietic transition (EHT). During EHT, transitioning cells proliferate and undergo progressive changes in gene expression culminating in the new cell identity with corresponding changes in function, phenotype and morphology. However, the metabolic pathways fueling this transition remain unclear. We show here that glutamine is a crucial regulator of EHT and a rate limiting metabolite in the hematopoietic differentiation of HE cells. Intriguingly, different hematopoietic lineages require distinct derivatives of glutamine. While both derivatives, α-ketoglutarate and nucleotides, are required for early erythroid differentiation of HE during glutamine deprivation, lymphoid differentiation relies on α-ketoglutarate alone. Furthermore, treatment of HE cells with α-ketoglutarate in glutamine-free conditions pushes their differentiation towards lymphoid lineages both in vitro and in vivo, following transplantation into NSG mice. Thus, we report an essential role for glutamine metabolism during EHT, regulating both the emergence and the specification of hematopoietic cells through its various derivatives.

DOI: https://doi.org/10.1038/s41598-021-97194-7
Mol Cell. 2021 Aug 27. pii: S1097-2765(21)00645-6. [Epub ahead of print]

The context-specific roles of urea cycle enzymes in tumorigenesis.

Emma Hajaj, Marco Sciacovelli, Christian Frezza, Ayelet Erez.

The expression of the urea cycle (UC) proteins is dysregulated in multiple cancers, providing metabolic benefits to tumor survival, proliferation, and growth. Here, we review the main changes described in the expression of UC enzymes and metabolites in different cancers at various stages and suggest that these changes are dynamic and should hence be viewed in a context-specific manner. Understanding the evolvability in the activity of the UC pathway in cancer has implications for cancer-immune cell interactions and for cancer diagnosis and therapy.

DOI: https://doi.org/10.1016/j.molcel.2021.08.005
Cancer Res. 2021 Sep 01. 81(17): 4399-4401

Patient-Derived Xenografts to Study Cancer Metabolism: When Does X Mark the Spot?

Christopher S Nabel, Matthew G Vander Heiden.

A major goal of cancer research is to understand the requirements for cancer growth and progression that can be exploited to treat patients. Model systems reduce the complexity and heterogeneity of human cancers to explore therapeutic hypotheses, however, some relevant aspects of human biology are not well represented by certain models, complicating the translation of preclinical findings to help patients. Here we discuss the advantages and limitations of patient-derived xenografts as a model system to study cancer metabolism, offering a framework to best use these models to address different types of metabolism-specific research questions.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-0770
World J Gastrointest Oncol. 2021 Aug 15. 13(8): 758-771

Metabolism-associated genes in occurrence and development of gastrointestinal cancer: Latest progress and future prospect.

Yan-Dong Miao, Lin-Jie Mu, Deng-Hai Mi.

  Gastrointestinal (GI) cancer remains one of the most prevalent cancers in the world. The occurrence and progression of GI cancer involve multiple events. Metabolic reprogramming is one of the hallmarks of cancer and is intricately related to tumorigenesis. Many metabolic genes are involved in the occurrence and development of GI cancer. Research approaches combining tumor genomics and metabolomics are more likely to provide deeper insights into this field. In this paper, we review the roles of metabolism-associated genes, especially those involved in the regulation pathways, in the occurrence and progression of GI cancer. We provide the latest progress and future prospect into the different molecular mechanisms of metabolism-associated genes involved in the occurrence and development of GI cancer.

Keywords:  Colorectal cancer; Gastric cancer; Gastrointestinal cancer; Metabolism-associated genes

DOI:  https://doi.org/10.4251/wjgo.v13.i8.758
Br J Cancer. 2021 Aug 30.

Atorvastatin facilitates chemotherapy effects in metastatic triple-negative breast cancer.

Juan Luis Gomez Marti, Colin H Beckwitt, Amanda M Clark, Alan Wells.

BACKGROUND: Metastatic triple-negative breast cancer (mTNBC) is treated mainly with chemotherapy. However, resistance frequently occurs as tumours enter dormancy. Statins have been suggested as effective against cancer but as they prolong and promote dormancy, it is an open question of whether the concomitant use would interfere with chemotherapy in primary and mTNBC. We examined this question in animal models and clinical correlations.
METHODS: We used a xenograft model of spontaneous metastasis to the liver from an ectopic tumour employing a mTNBC cell line. Atorvastatin was provided to sensitise metastatic cells, followed by chemotherapy. The effects of statin usage on outcomes in women with metastatic breast cancer was assessed respectively by querying a database of those diagnosed from 1999 to 2019.
RESULTS: Atorvastatin had limited influence on tumour growth or chemotherapy effects in ectopic primary tumours. Interestingly, atorvastatin was additive with doxorubicin (but not paclitaxel) when targeting liver metastases. E-cadherin-expressing, dormant, breast cancer cells were resistant to the use of either statins or chemotherapy as compared to wild-type cells; however, the combination of both did lead to increased cell death. Although prospective randomised studies are needed for validation, our retrospective clinical analysis suggested that patients on statin treatment could experience prolonged dormancy and overall survival; still once the tumour recurred progression was not affected by statin use.
CONCLUSION: Atorvastatin could be used during adjuvant chemotherapy and also in conjunction with metastatic chemotherapy to reduce mTNBC cancer progression. These preclinical data establish a rationale for the development of randomised studies.

DOI: https://doi.org/10.1038/s41416-021-01529-0
Cell Death Differ. 2021 Aug 31.

Organelle-specific regulation of ferroptosis.

Xin Chen, Rui Kang, Guido Kroemer, Daolin Tang.

Ferroptosis, a cell death modality characterized by iron-dependent lipid peroxidation, is involved in the development of multiple pathological conditions, including ischemic tissue damage, infection, neurodegeneration, and cancer. The cellular machinery responsible for the execution of ferroptosis integrates multiple pro-survival or pro-death signals from subcellular organelles and then 'decides' whether to engage the lethal process or not. Here, we outline the evidence implicating different organelles (including mitochondria, lysosomes, endoplasmic reticulum, lipid droplets, peroxisomes, Golgi apparatus, and nucleus) in the ignition or avoidance of ferroptosis, while emphasizing their potential relevance for human disease and their targetability for pharmacological interventions.

DOI: https://doi.org/10.1038/s41418-021-00859-z
Pharmacol Rep. 2021 Aug 30.

Endogenous estrogens-breast cancer and chemoprevention.

Beata Starek-Świechowicz, Bogusława Budziszewska, Andrzej Starek.

  Breast cancer is the most common female malignancy and the second leading cause of cancer related deaths. It is estimated that about 40% of all cancer in women is hormonally mediated. Both estrogens and androgens play critical roles in the initiation and development of breast cancer. Estrogens influence normal physiological growth, proliferation, and differentiation of breast tissues, as well as the development and progression of breast malignancy. Breast cancer is caused by numerous endo- and exogenous risk factors. The paper presents estrogen metabolism, in particular 17β-estradiol and related hormones. The mechanisms of estrogen carcinogenesis include the participation of estrogen receptors, the genotoxic effect of the estrogen metabolites, and epigenetic processes that are also presented. The role of reactive oxygen species in breast cancer has been described. It called attention to a role of numerous signaling pathways in neoplastic transformation. Chemoprotective agents, besides other phytoestrogens, classical antioxidants, synthetic compounds, and their mechanisms of action have been shown.

Keywords:  Breast cancer; Chemopreventive agents; Endogenous estrogens; Estrogen metabolism

DOI:  https://doi.org/10.1007/s43440-021-00317-0
Nano Lett. 2021 Sep 02.

Nanoparticle-Mediated Inhibition of Mitochondrial Glutaminolysis to Amplify Oxidative Stress for Combination Cancer Therapy.

Lei Xu, Rui Xu, Phei Er Saw, Jun Wu, Si-Xue Cheng, Xiaoding Xu.

  Selective amplification of reactive oxygen species (ROS) generation in tumor cells has been recognized as an effective strategy for cancer therapy. However, an abnormal tumor metabolism, especially the mitochondrial glutaminolysis, could promote tumor cells to generate high levels of antioxidants (e.g., glutathione) to evade ROS-induced damage. Here, we developed a tumor-targeted nanoparticle (NP) platform for effective breast cancer therapy via combining inhibition of mitochondrial glutaminolysis and chemodynamic therapy (CDT). This NP platform is composed of bovine serum albumin (BSA), ferrocene, and purpurin. After surface decoration with a tumor-targeting aptamer and then intravenous administration, this NP platform could target tumor cells and release ferrocene to catalyze hydrogen peroxide (H2O2) into the hydroxyl radical (·OH) for CDT. More importantly, purpurin could inhibit mitochondrial glutaminolysis to concurrently prevent the nutrient supply for tumor cells and disrupt intracellular redox homeostasis for enhanced CDT, ultimately leading to the combinational inhibition of tumor growth.

Keywords:  Reactive oxygen species; chemodynamic therapy; combination cancer therapy; glutaminolysis; nanoparticle

DOI:  https://doi.org/10.1021/acs.nanolett.1c02073