bims-oxygme 2025-02-09 papers

Issue of 2025–02–09
five papers selected by
Onurkan Karabulut, Berkeley City College

Cell Genom. 2025 Jan 30. pii: S2666-979X(25)00020-5. [Epub ahead of print] 100764

Defining hypoxia in cancer: A landmark evaluation of hypoxia gene expression signatures.

Matteo Di Giovannantonio, Fiona Hartley, Badran Elshenawy, Alessandro Barberis, Dan Hudson, Hana S Shafique, Vincent E S Allott, David A Harris, Simon R Lord, Syed Haider, Adrian L Harris, Francesca M Buffa, Benjamin H L Harris.

Tumor hypoxia drives metabolic shifts, cancer progression, and therapeutic resistance. Challenges in quantifying hypoxia have hindered the exploitation of this potential "Achilles' heel." While gene expression signatures have shown promise as surrogate measures of hypoxia, signature usage is heterogeneous and debated. Here, we present a systematic pan-cancer evaluation of 70 hypoxia signatures and 14 summary scores in 104 cell lines and 5,407 tumor samples using 472 million length-matched random gene signatures. Signature and score choice strongly influenced the prediction of hypoxia in vitro and in vivo. In cell lines, the Tardon signature was highly accurate in both bulk and single-cell data (94% accuracy, interquartile mean). In tumors, the Buffa and Ragnum signatures demonstrated superior performance, with Buffa/mean and Ragnum/interquartile mean emerging as the most promising for prospective clinical trials. This work delivers recommendations for experimental hypoxia detection and patient stratification for hypoxia-targeting therapies, alongside a generalizable framework for signature evaluation.

Keywords: biomarkers; gene signature; hypoxia; hypoxia-targeting therapies; patient stratification; radiotherapy; signature scores; single cell; transcriptomics; tumorigenesis

DOI: https://doi.org/10.1016/j.xgen.2025.100764

J Cell Mol Med. 2025 Feb;29(3): e70398

GPX3 Overexpression Ameliorates Cardiac Injury Post Myocardial Infarction Through Activating LSD1/Hif1α Axis.

Qi-Qi Jiang, Chong Du, Ling-Ling Qian, Tian-Kai Shan, Yu-Lin Bao, Ling-Feng Gu, Si-Bo Wang, Tong-Tong Yang, Liu-Hua Zhou, Ze-Mu Wang, Ye He, Qi-Ming Wang, Hao Wang, Ru-Xing Wang, Lian-Sheng Wang.

Myocardial infarction (MI) often results in significant loss of cardiomyocytes (CMs), contributing to adverse ventricular remodelling and heart failure. Therefore, promoting CM survival during the acute stage of MI is crucial. This study aimed to investigate the potential role of GPX3 in cardiac repair following MI. First, plasma GPX3 levels were measured in patients with acute MI (AMI), and myocardial GPX3 expression was assessed in a mouse MI model. Furthermore, the effects of GPX3 on MI were investigated through CM-specific overexpression or knockdown in vitro and in vivo models. RNA sequencing and subsequent experiments were performed to uncover the molecular mechanisms underlying GPX3-related effects. Multi-omics database analysis and experimental verification revealed a significant upregulation of GPX3 expression in ischemic myocardium following MI and in CMs exposed to oxygen-glucose deprivation (OGD). Immunofluorescence results further confirmed elevated cytoplasmic GPX3 expression in CMs under hypoxic conditions. In vitro, GPX3 overexpression mitigated reactive oxygen species (ROS) production and enhanced CM survival during hypoxia, while GPX3 knockdown inhibited these processes. In vivo, CM-specific GPX3 overexpression in the infarct border zone significantly attenuated CM apoptosis and alleviated myocardial injury, promoting cardiac repair and long-term functional recovery. Mechanistically, GPX3 overexpression upregulated LSD1 and Hif1α protein expression, and rescue experiments confirmed the involvement of the LSD1/Hif1α pathway in mediating the protective effects of GPX3. Overall, our findings suggest that GPX3 exerts a protective role in ischemic myocardium post-MI, at least partially through the LSD1/Hif1α axis, highlighting its potential as a therapeutic target for MI treatment.

Keywords: GPX3; Hif1α; LSD1; cardiomyocyte apoptosis; myocardial infarction; oxidative stress

DOI: https://doi.org/10.1111/jcmm.70398

Clin Cancer Res. 2025 Feb 03.

Mitochondria-targeting of oxidative phosphorylation inhibitors to alleviate hypoxia and enhance anticancer treatment efficacy.

Anne P M Beerkens, Sandra Heskamp, Flavia V Reinema, Gosse J Adema, Paul N Span, Johan Bussink.

Hypoxia is a common feature of solid tumors and is associated with a poor response to anticancer therapies. Hypoxia also induces metabolic changes, such as a switch to glycolysis. This glycolytic switch causes acidification of the tumor microenvironment (TME), thereby attenuating the anticancer immune response. A promising therapeutic strategy to reduce hypoxia and thereby sensitize tumors to irradiation and/or antitumor immune responses is pharmacological inhibition of oxidative phosphorylation (OXPHOS). Several OXPHOS inhibitors (OXPHOSi) have been tested in clinical trials. However, moderate responses and/or substantial toxicity has hampered clinical implementation. OXPHOSi tested in clinical trials inhibit the oxidative metabolism in tumor cells as well as healthy cells. Therefore, new strategies are needed to improve the efficacy of OXPHOSi while minimizing side effects. To enhance the therapeutic window, available OXPHOSi have, for instance, been conjugated to triphenylphosphonium (TPP+) to preferentially target the mitochondria of cancer cells, resulting in increased tumor uptake compared to healthy cells, as cancer cells have a higher mitochondrial membrane potential. However, OXPHOS inhibition also induces reactive oxygen species (ROS), and subsequent antioxidant responses, which may influence the efficacy of therapies, such as platinum-based chemotherapy and radiotherapy. Here, we review the limitations of the clinically tested OXPHOSi metformin, atovaquone, tamoxifen, BAY 87-2243 and IACS-010759 and the potential of mito-targeted OXPHOSi and their influence on ROS production. Furthermore, the effect of the mitochondria-targeting moiety TPP+ on mitochondria is discussed as this affects mitochondrial bioenergetics.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-3296

Toxicol Appl Pharmacol. 2025 Feb 04. pii: S0041-008X(25)00035-3. [Epub ahead of print] 117259

Effects of hypoxia and iron on ascorbic acid-mediated cytotoxicity in prostate cancer cell lines.

Samiksha Deme, Ida Ramazeni, Jonathan Coulter, Channing Paller, Joseph Bressler.

Ascorbic acid (ASC) has long been proposed as a potential cancer co-treatment due to its specific toxicity towards cancer cells, but discrepancies between in vitro and in vivo studies suggest that external factors may modulate its cytotoxicity. Here, we investigate the impact of hypoxia and iron on the therapeutic effectiveness of ASC on prostate cancer cell lines. Hypoxia-induced increases in the EC50 of ASC in the prostate cancer cell lines PC-3, DU 145, LNCaP, and CWR22Rv1 but not in the prostate non-cancer cell lines RWPE-1 and TERT-PrECs. The synthetic androgen dihydrotestosterone did not modify ASC's effectiveness in either normoxia or hypoxia, which was tested because both early and advanced prostate cancer maintain the androgen receptor pathway. The effects of hypoxia on cytotoxicity depend on the drug. Hypoxia did not affect the EC50 for the DNA-damaging agent etoposide but decreased the sensitivity for the anti-microtubule agent paclitaxel in PC-3 and DU 145 cells. Although hypoxic cells were iron deficient, adding iron back to cells did not reverse the effects of the hypoxic atmosphere. Interestingly, the EC50 for ASC was approximately two-fold higher in iron-treated cells than non‑iron-treated cells for the PC-3 line. The higher EC50 was not observed by knocking down ferritin heavy chain mRNA. In summary, both hypoxia and iron attenuate the effectiveness of high concentrations of ASC in prostate cancer cell lines, which may affect the therapeutic benefit of ASC for prostate cancer patients.

DOI: https://doi.org/10.1016/j.taap.2025.117259