bims-nurfca 2023-03-12 papers

Issue of 2023–03–12
three papers selected by
Caner Geyik, Istinye University

J Med Chem. 2023 Mar 09.

ARE-PROTACs Enable Co-degradation of an Nrf2-MafG Heterodimer.

Jianai Ji, Sinan Ma, Yuxuan Zhu, Jinglong Zhao, Yuanyuan Tong, Qidong You, Zhengyu Jiang.

Proteolysis-targeting chimera (PROTAC) technology has emerged as a potential strategy to degrade "undruggable" proteins in recent years. Nrf2, an aberrantly activated transcription factor in cancer, is generally considered undruggable as lacking active sites or allosteric pockets. Here, we constructed the chimeric molecule C2, which consists of an Nrf2-binding element and a CRBN ligand, as a first-in-class Nrf2 degrader. Surprisingly, C2 was found to selectively degrade an Nrf2-MafG heterodimer simultaneously via the ubiquitin-proteasome system. C2 impeded Nrf2-ARE transcriptional activity significantly and improved the sensitivity of NSCLC cells to ferroptosis and therapeutic drugs. The degradation character of ARE-PROTACs suggests that the PROTAC hijacking the transcription element of TFs could achieve co-degradation of the transcription complex.

DOI: https://doi.org/10.1021/acs.jmedchem.2c01909

Cell Mol Gastroenterol Hepatol. 2023 Mar 07. pii: S2352-345X(23)00038-3. [Epub ahead of print]

Ferroptosis suppressor protein 1 inhibition promotes tumor ferroptosis and anti-tumor immune responses in liver cancer.

Jacinth Wing-Sum Cheu, Derek Lee, Qidong Li, Chi Ching Goh, Macus Hao-Ran Bao, Vincent Wai-Hin Yuen, Misty Shuo Zhang, Chunxue Yang, Cerise Yuen-Ki Chan, Aki Pui-Wah Tse, Grace Fu-Wan Sit, Cindy Xinqi Liu, Irene Oi-Lin Ng, Chun-Ming Wong, Carmen Chak-Lui Wong.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with dreadful clinical outcome. Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) are the only FDA-approved therapeutic options for advanced HCC patients with limited therapeutic success. Ferroptosis is a form of immunogenic and regulated cell death (RCD) caused by chain reaction of iron-dependent lipid peroxidation. Coenzyme Q10 (CoQ10)/ferroptosis suppressor protein 1 (FSP1) axis was recently identified as a novel protective mechanism against ferroptosis. We would like to explore whether FSP1 could be a potential therapeutic target for HCC.
METHODS: FSP1 expression in human HCC and paired non-tumorous (NT) tissue samples were determined by RT-qPCR followed by clinicopathologic correlation and survival studies. Regulatory mechanism for FSP1 was determined using chromatin immunoprecipitation (ChIP). The hydrodynamic tail vein injection (HDTVi) model was used for HCC induction to evaluate the efficacy of FSP1 inhibitor (iFSP1) in vivo. Single-cell RNA sequencing (scRNA-seq) revealed the immunomodulatory effects of iFSP1 treatment.
RESULTS: We showed that HCC cells greatly rely on the CoQ10/FSP1 system to overcome ferroptosis. We found that FSP1 was significantly overexpressed in human HCC and is regulated by kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway. FSP1 inhibitor iFSP1 effectively reduced HCC burden and profoundly increased immune infiltrates including dendritic cells (DCs), macrophages, and T cells. We also demonstrated that iFSP1 worked synergistically with immunotherapies to suppress HCC progression.
CONCLUSIONS: We identified FSP1 as a novel, vulnerable therapeutic target in HCC. The inhibition of FSP1 potently induced ferroptosis which promoted innate and adaptive anti-tumor immune responses and effectively suppressed HCC tumor growth. FSP1 inhibition therefore represents a new therapeutic strategy for HCC.

Keywords: Hepatocellular carcinoma; immunogenic cell death; lipid peroxidation; regulated cell death

DOI: https://doi.org/10.1016/j.jcmgh.2023.03.001

Cancers (Basel). 2023 Mar 03. pii: 1586. [Epub ahead of print]15(5):

Zinc Finger Protein 90 Knockdown Promotes Cisplatin Sensitivity via Nrf2/HO-1 Pathway in Ovarian Cancer Cell.

Ching-Hu Wu, Chien-Wei Feng, Chiu-Lin Wang, Zhi-Hong Wen, Cheng-Yu Long, Feng-Hsiang Tang.

Our study discussed the role of Zfp90 in ovarian cancer (OC) cell lines' sensitivity to cisplatin. We used two OC cell lines, SK-OV-3 and ES-2, to evaluate their role in cisplatin sensitization. The protein levels of p-Akt, ERK, caspase 3, Bcl-2, Bax, E-cadherin, MMP-2, MMP-9 and other drug resistance-related molecules, including Nrf2/HO-1, were discovered in the SK-OV-3 and ES-2 cells. We also used a human ovarian surface epithelial cell to compare the effect of Zfp90. Our outcomes indicated that cisplatin treatment generates reactive oxygen species (ROS) that modulate apoptotic protein expression. The anti-oxidative signal was also stimulated, which could hinder cell migration. The intervention of Zfp90 could greatly improve the apoptosis pathway and block the migrative pathway to regulate the cisplatin sensitivity in the OC cells. This study implies that the loss of function of Zfp90 might promote cisplatin sensitization in OC cells via regulating the Nrf2/HO-1 pathway to enhance cell apoptosis and inhibit the migrative effect in both SK-OV-3 and ES-2 cells.

Keywords: apoptosis; cisplatin sensitivity; nuclear factor E2-related factor 2; ovarian cancer; zinc finger protein 90

DOI: https://doi.org/10.3390/cancers15051586