bims-nurfca 2023-02-19 papers

Issue of 2023–02–19
three papers selected by
Caner Geyik, Istinye University

Redox Biol. 2023 Apr;pii: S2213-2317(23)00033-2. [Epub ahead of print]60 102632

Association of NRF2 with HIF-2α-induced cancer stem cell phenotypes in chronic hypoxic condition.

Steffanus Pranoto Hallis, Seung Ki Kim, Jin-Hee Lee, Mi-Kyoung Kwak.

The acquisition of the cancer stem cell (CSC) properties is often mediated by the surrounding microenvironment, and tumor hypoxia is considered an important factor for CSC phenotype development. High levels of NRF2 (Nuclear Factor Erythroid 2-Like 2; NFE2L2), a transcription factor that maintains cellular redox balance, have been associated with facilitated tumor growth and therapy resistance. In this study, we investigated the role of NRF2 in hypoxia-induced CSC phenotypes in colorectal cancer cells. Chronic hypoxia for 72 h resulted in CSC phenotypes, including elevation of krupple-like factor 4 (KLF4) and octamer-binding transcription factor 4 (OCT4), and an increase in cancer migration and spheroid growth with concomitant hypoxia-inducible factor 2α (HIF-2α) accumulation. All these chronic hypoxia-induced CSC properties were attenuated following HIF-2α-specific silencing. In this chronic hypoxia model, NRF2 inhibition by shRNA-based silencing or brusatol treatment blocked HIF-2α accumulation, which consequently resulted in decreased CSC marker expression and inhibition of CSC properties such as spheroid growth. In contrast, NRF2 overactivation by genetic or chemical approach enhanced the chronic hypoxia-induced HIF-2α accumulation and cancer migration. As a molecular mechanism of the NRF2-inhibition-mediated HIF-2α dysregulation, we demonstrated that miR-181a-2-3p, whose expression is elevated in NRF2-silenced cells, targeted the HIF-2α 3'UTR and subsequently suppressed the chronic hypoxia-induced HIF-2α and CSC phenotypes. The miR-181a-2-3p inhibitor treatment in NRF2-silenced cells could restore the levels of HIF-2α and CSC markers, and increased cancer migration and sphere formation under chronic hypoxia. In line with this, the miR-181a-2-3p inhibitor transfection could increase tumorigenicity of NRF2-silenced colorectal cancer cells. Collectively, our study suggests the involvement of NRF2/miR181a-2-3p signaling in the development of HIF-2α-mediated CSC phenotypes in sustained hypoxic environments.

Keywords: Cancer stem cell phenotype; Chronic hypoxia; HIF-2α; NRF2; miR-181a-2-3p

DOI: https://doi.org/10.1016/j.redox.2023.102632

Lab Invest. 2022 Dec;pii: S0023-6837(22)03981-2. [Epub ahead of print]102(12): 1335-1345

Brusatol sensitizes endometrial hyperplasia and cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism.

Meiyan Hu, Di Sun, Jing Yu, Yue Fu, Zuoshu Qin, Baozhu Huang, Qiuju Zhang, Xiong Chen, Youheng Wei, Huiting Zhu, Yue Wang, Youji Feng, Wenxin Zheng, Hong Liao, Jingjie Li, Sufang Wu, Zhenbo Zhang.

Progestin resistance is the main obstacle for the conservative therapy to maintain fertility in women with endometrial cancer. Brusatol was identified as an inhibitor of the NRF2 pathway; however, its impact on progestin resistance and the underlying mechanism remains unclear. Here, we found that brusatol sensitized endometrial cancer to progestin by suppressing NRF2-TET1-AKR1C1-mediated progestin metabolism. Brusatol transcriptionally suppressed AKR1C1 via modifying the hydroxymethylation status in its promoter region through TET1 inhibition. Suppression of AKR1C1 by brusatol resulted in decreased progesterone catabolism and maintained potent progesterone to inhibit endometrial cancer growth. This inhibition pattern has also been found in the established xenograft mouse and organoid models. Aberrant overexpression of AKR1C1 was found in paired endometrial hyperplasia and cancer samples from the same individuals with progestin resistance, whereas attenuated or loss of AKR1C1 was observed in post-treatment samples with well progestin response as compared with paired pre-treatment tissues. Our findings suggest that AKR1C1 expression pattern may serve as an important biomarker of progestin resistance in endometrial cancer. For precancerous/endometrial cancer patients with fertility maintain desire, progestin resistance is the main obstacle of conservative therapy. The authors found that brusatol, as a natural compound, suppresses progestin metabolism through regulating the NRF2-TET1-AKR1C1 pathway to sensitize precancerous/endometrial cancers to progestin and relieve progestin resistance. This study indicates that progestin combined with brusatol may enhance the treatment effects and that AKR1C1 expression patterns may serve as an important biomarker of progestin resistance in endometrial cancer.

DOI: https://doi.org/10.1038/s41374-022-00816-5

J Nutr Biochem. 2023 Feb 13. pii: S0955-2863(23)00017-7. [Epub ahead of print] 109283

Targeted Tumor Killing by Pomegranate Polyphenols: Pro-oxidant Role of a Classical Antioxidant.

Sudeshna Mukherjee, Payal Gupta, Sayan Ghosh, Sreetama Choudhury, Ankur Das, Manisha Ahir, Arghya Adhikary, Sreya Chattopadhyay.

One of the key biochemical features that distinguish a cancer cell from normal cells is its persistent pro-oxidative state that leads to intrinsic oxidative stress. Malignant cells have evolved sophisticated adaptation systems that involve high dependency on antioxidant functions and upregulation of pro-survival molecules to counteract the deleterious effects of reactive species and to maintain dynamic redox balance. This situation renders them vulnerable to further oxidative challenge by exogenous agents. In the present study, we advocated that pomegranate polyphenols act as pro-oxidants and trigger ROS-mediated apoptosis in cancer cells. With the help of both in vitro and in vivo models, we have established that pomegranate fruit extract (PFE) can cause significant reduction in tumor proliferation while leaving normal tissues and cells unharmed. Administration of PFE (0.2% v/v) in EAC-bearing mice for 3 weeks, inhibited Nrf2-ARE signaling cascade, increased intracellular ROS content, altered GSH cycle thereby activating ROS-induced apoptotic pathway in EAC cells. Moreover, PFE mitigated epithelial to mesenchymal transition (EMT) and migration in triple negative breast cancer cells (MDA-MB 231 cells) by down-regulating NF-κB. Pre-treatment of tumor cells with N-acetyl cysteine (NAC) protected these cells from undergoing PFE-induced apoptosis while siRNA-mediated silencing of Nrf2 and NF-κB in tumor cells increased the cytotoxic potential and pro-oxidative activity of PFE, indicating a clear role of these transcription factors in orchestrating the anti-cancer/pro-oxidative properties of PFE. The seminal findings provided may be exploited to develop potential therapeutic targets for selective killing of malignant cells.

Keywords: NF-κB; Nrf2; Pomegranate; ROS; antioxidants; apoptosis; cancer; pro-oxidants; toxicity

DOI: https://doi.org/10.1016/j.jnutbio.2023.109283