Reactive oxygen species (ROS) play important roles in tissue homeostasis, cellular signaling, differentiation, and survival. In this review, we discuss the types ofROS, their impact on cellular ...processes, and their pro- and antitumorigenic effects. Further, we discuss recent advances in our understanding of both endogenous and exogenous antioxidants in tumorigenic processes. Finally, wediscuss how aberrant activation of antioxidant programs by the transcription factor NFE2-related factor 2 (NRF2) influences tumorigenesis and metastasis, and where the current gaps in our knowledge remain.
New tools allow invivo measurements of ROS in tumors.Mouse modeling and genetic screening approaches have revealed novel complexities and redundancies in endogenous antioxidant systems.Exogenous antioxidants may promote cancer through complex mechanisms.Aberrant NRF2 activation has diverse, and sometimes contradictory, impacts on tumor growth and metastasis.Tissue of origin, tumor stage, and the microenvironment greatly influence the influence of ROS on cancer.
The regulation of oxidative stress is an important factor in both tumour development and responses to anticancer therapies. Many signalling pathways that are linked to tumorigenesis can also regulate ...the metabolism of reactive oxygen species (ROS) through direct or indirect mechanisms. High ROS levels are generally detrimental to cells, and the redox status of cancer cells usually differs from that of normal cells. Because of metabolic and signalling aberrations, cancer cells exhibit elevated ROS levels. The observation that this is balanced by an increased antioxidant capacity suggests that high ROS levels may constitute a barrier to tumorigenesis. However, ROS can also promote tumour formation by inducing DNA mutations and pro-oncogenic signalling pathways. These contradictory effects have important implications for potential anticancer strategies that aim to modulate levels of ROS. In this Review, we address the controversial role of ROS in tumour development and in responses to anticancer therapies, and elaborate on the idea that targeting the antioxidant capacity of tumour cells can have a positive therapeutic impact.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
3.
Glutathione and its precursors in cancer Asantewaa, Gloria; Harris, Isaac S
Current opinion in biotechnology,
April 2021, 2021-Apr, 2021-04-00, 20210401, Letnik:
68
Journal Article
Recenzirano
Buffering oxidative stress is as a crucial requirement for tumorigenesis. Antioxidant is a term reserved for molecules that quench reactive oxygen species (ROS) and alleviate oxidative stress. The ...details regarding antioxidant synthesis, their utilization to eliminate ROS, and their ability to promote different stages of tumorigenesis are unclear. Here, we focus on glutathione (GSH), the most abundant antioxidant in the cell, and its precursor amino acids (cysteine, glutamate, and glycine). Even though GSH was discovered more than a century ago, continued research into this antioxidant has provided answers to longstanding questions while also posing new ones.
Mammary epithelial cells transition between periods of proliferation and quiescence during development, menstrual cycles, and pregnancy, and as a result of oncogenic transformation. Utilizing an ...organotypic 3D tissue culture model coupled with quantitative metabolomics and proteomics, we identified significant differences in glutamate utilization between proliferating and quiescent cells. Relative to quiescent cells, proliferating cells catabolized more glutamate via transaminases to couple non-essential amino acid (NEAA) synthesis to α-ketoglutarate generation and tricarboxylic acid (TCA) cycle anaplerosis. As cells transitioned to quiescence, glutamine consumption and transaminase expression were reduced, while glutamate dehydrogenase (GLUD) was induced, leading to decreased NEAA synthesis. Highly proliferative human tumors display high transaminase and low GLUD expression, suggesting that proliferating cancer cells couple glutamine consumption to NEAA synthesis to promote biosynthesis. These findings describe a competitive and partially redundant relationship between transaminases and GLUD, and they reveal how coupling of glutamate-derived carbon and nitrogen metabolism can be regulated to support cell proliferation.
Display omitted
•Proliferating cells catabolize glutamate via transaminases to synthesize NEAAs•Glutamate dehydrogenase is induced in quiescence, and NEAA synthesis is reduced•Highly proliferative breast tumors have high transaminase and low GLUD expression•Transaminases and GLUD display a competitive and partially redundant relationship
Using a 3D tissue culture model, Coloff et al. identify differences in glutamate utilization in proliferating and quiescent mammary epithelial cells. These studies demonstrate that highly proliferative normal and breast cancer cells couple glutamine-derived carbon and nitrogen metabolism by suppressing glutamate dehydrogenase and synthesizing NEAAs via transaminases.
Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer ...initiation. Genetic loss of Gclm prevents a tumor’s ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable potentially due to compensation from alternative antioxidant pathways. Remarkably, combined inhibition of GSH and thioredoxin antioxidant pathways leads to a synergistic cancer cell death in vitro and in vivo, demonstrating the importance of these two antioxidants to tumor progression and as potential targets for therapeutic intervention.
Display omitted
•The GSH antioxidant pathway is required for cancer initiation•After cancer initiation, GSH is dispensable due to alternative antioxidant pathways•The TXN antioxidant pathway is upregulated in tumors•Inhibition of both GSH and TXN pathways causes synergistic cancer cell death
Harris et al. show that the antioxidant glutathione (GSH) is required for cancer initiation but not for established tumors partly due to upregulation of the thioredoxin (TXN) antioxidant pathway in the latter. Consequently, blocking both GSH and TXN pathways synergistically inhibits tumor growth.
Regulation of cancer cell metabolism Mak, Tak W; Cairns, Rob A; Harris, Isaac S
Nature reviews. Cancer,
02/2011, Letnik:
11, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are ...fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Cysteine is required for maintaining cellular redox homeostasis in both normal and transformed cells. Deprivation of cysteine induces the iron-dependent form of cell death known as ferroptosis; ...however, the metabolic consequences of cysteine starvation beyond impairment of glutathione synthesis are poorly characterized. Here, we find that cystine starvation of non-small-cell lung cancer cell lines induces an unexpected accumulation of γ-glutamyl-peptides, which are produced due to a non-canonical activity of glutamate-cysteine ligase catalytic subunit (GCLC). This activity is enriched in cell lines with high levels of NRF2, a key transcriptional regulator of GCLC, but is also inducible in healthy murine tissues following cysteine limitation. γ-glutamyl-peptide synthesis limits the accumulation of glutamate, thereby protecting against ferroptosis. These results indicate that GCLC has a glutathione-independent, non-canonical role in the protection against ferroptosis by maintaining glutamate homeostasis under cystine starvation.
Display omitted
•Cystine starvation induces γ-glutamyl-peptide accumulation in NSCLC cells•GCLC catalyzes γ-glutamyl-peptide synthesis via a GSH-independent mechanism•NRF2 protects against ferroptosis via γ-glutamyl-peptide synthesis•γ-glutamyl-peptide synthesis prevents ferroptosis by reducing glutamate stress
GCLC catalyzes the first step in glutathione synthesis via the ligation of cysteine with glutamate. Kang et al. demonstrate that under cysteine-limiting conditions, GCLC instead ligates glutamate with alternative amino acids, thereby scavenging glutamate to protect against ferroptosis.
Cells respond to amino acid depletion by activating stress responses. A recent study by Swanda et al. reveals that a decrease in lysosomal cystine triggers a novel stress response that ...transcriptionally activates ATF4 and protects cells from ferroptosis. A synthetic mRNA, CysRx, can prevent ATF4 activation and enhance antitumor effects.
Cancer cell survival is dependent on oxidative-stress defenses against reactive oxygen species (ROS) that accumulate during tumorigenesis. Here, we show a non-canonical oxidative-stress defense ...mechanism through TRPA1, a neuronal redox-sensing Ca2+-influx channel. In TRPA1-enriched breast and lung cancer spheroids, TRPA1 is critical for survival of inner cells that exhibit ROS accumulation. Moreover, TRPA1 promotes resistance to ROS-producing chemotherapies, and TRPA1 inhibition suppresses xenograft tumor growth and enhances chemosensitivity. TRPA1 does not affect redox status but upregulates Ca2+-dependent anti-apoptotic pathways. NRF2, an oxidant-defense transcription factor, directly controls TRPA1 expression, thus providing an orthogonal mechanism for protection against oxidative stress together with canonical ROS-neutralizing mechanisms. These findings reveal an oxidative-stress defense program involving TRPA1 that could be exploited for targeted cancer therapies.
Display omitted
•TRPA1 is overexpressed in cancer and mediates a non-canonical ROS defense program•TRPA1 promotes ROS tolerance via induction of Ca2+-dependent anti-apoptotic pathways•NRF2, an oxidant-defense transcription factor, directly controls TRPA1 expression•Targeting TRPA1 reduces xenograft tumor growth and enhances chemosensitivity
Takahashi et al. show that TRPA1, a neuronal redox-sensing Ca2+-influx channel overexpressed in human cancer, upregulates Ca2+-dependent anti-apoptotic pathways to promote ROS resistance. NRF2 directly controls TRPA1 expression and TRPA1 inhibition suppresses xenograft tumor growth and enhances chemosensitivity.
Regulation of antioxidants in cancer Hecht, Fabio; Zocchi, Marco; Alimohammadi, Fatemeh ...
Molecular cell,
01/2024, Letnik:
84, Številka:
1
Journal Article
Recenzirano
Scientists in this field often joke, “If you don’t have a mechanism, say it’s ROS.” Seemingly connected to every biological process ever described, reactive oxygen species (ROS) have numerous ...pleiotropic roles in physiology and disease. In some contexts, ROS act as secondary messengers, controlling a variety of signaling cascades. In other scenarios, they initiate damage to macromolecules. Finally, in their worst form, ROS are deadly to cells and surrounding tissues. A set of molecules with detoxifying abilities, termed antioxidants, is the direct counterpart to ROS. Notably, antioxidants exist in the public domain, touted as a “cure-all” for diseases. Research has disproved many of these claims and, in some cases, shown the opposite. Of all the diseases, cancer stands out in its paradoxical relationship with antioxidants. Although the field has made numerous strides in understanding the roles of antioxidants in cancer, many questions remain.
The paradoxical role of antioxidants in cancer has been a matter of intense debate in recent years. Here, we highlight the latest breakthroughs that shed light on the molecular mechanisms by which antioxidants are regulated in cancer to impact their initiation, progression, and metastatic capabilities.
PDF
