bims-nurfca 2022-12-11 papers

Issue of 2022–12–11
four papers selected by
Caner Geyik, Istinye University

Technol Cancer Res Treat. 2022 Jan-Dec;21:21 15330338221105736

Role of NRF2 in Colorectal Cancer Prevention and Treatment.

Jiaxiang Li, Dan Wang, Yifei Liu, Yanhong Zhou.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a basic leucine zipper protein that participates in a complex regulatory network in the body. The activation of NRF2 can prevent and treat colorectal cancer (CRC). A variety of natural compounds can activate NRF2 to inhibit oxidative stress and inflammation to prevent the occurrence and development of CRC, inhibit the proliferation of CRC cells and induce their apoptosis. However, some studies have also shown that it also has negative effects on CRC, such as overexpression of NRF2 can promote the growth of colorectal tumors and increase the drug resistance of chemotherapeutic drugs such as 5-fluorouracil and oxaliplatin. Therefore, inhibition of NRF2 can also be helpful in the treatment of CRC. In this study, we analyze the current research progress of NRF2 in CRC from various aspects to provide new ideas for prevention and treatment based on the NRF2 signaling pathway in CRC.

Keywords: colorectal cancer; inflammatory-associated colorectal cancer; nuclear factor E2-related factor 2; prevention; treatment

DOI: https://doi.org/10.1177/15330338221105736

Cell Mol Biol (Noisy-le-grand). 2022 Jul 31. 68(7): 160-164

CD147 Protein Expression and Temozolomide Resistance in Glioma Cells: An Ex vivo and In vivo Study.

Guo-Qiang Luo, Shuang Bai, Yan Hu, Hu Chen, Zhong-Jun Yan, Ling-Ling Fan.

It has been noted that temozolomide resistance occurs in a number of malignancies, including glioma, although the underlying cause of this is unknown. The goal of the study in vivo investigation to show that increased CD147 expression in glioma cells is a factor in their resistance to the chemotherapy drug temozolomide. Proliferation assays, TUNEL assays, reactive oxygen species assays, protein degradation assays, immunohistochemistry, Western blotting, quantitative polymerase chain reactions, and tumorigenicity assays were all carried out. Using the human protein atlas databases, the expression levels of CD147 in different kinds of malignancies were examined. For immunohistochemistry, a total of 7, 12, 19, 15, and 16 glioma samples were taken from para-carcinoma tissue, representing stage I, stage II, stage III, and stage IV gliomas, respectively. The expression of CD147 proteins is correlated with the tumor's aggressiveness. Cell development was slowed by suppressing the expression of the CD147 protein. The expression of the CD147 protein contributed to the emergence of temozolomide resistance. Expression of the CD147 protein reduced mRNA expression. The growth-inhibitory impact of temozolomide on glioma cells was enhanced by the suppression of CD147 protein. Nuclear factor E2-related factor 2 expression and CD147 protein expression showed a significant reciprocal connection with each other (p 0.0001, r2 = 0.3254). In glioma, resistance to temozolomide is due to overexpression of CD147 protein and induction of nuclear factor E2-related factor 2.

DOI: https://doi.org/10.14715/cmb/2022.68.7.26

Sci Rep. 2022 Dec 08. 12(1): 21265

Nrf2 and Parkin-Hsc70 regulate the expression and protein stability of p62/SQSTM1 under hypoxia.

Ferbian Milas Siswanto, Yumi Mitsuoka, Misato Nakamura, Ami Oguro, Susumu Imaoka.

Solid tumors often contain regions with very low oxygen concentrations or hypoxia resulting from altered metabolism, uncontrolled proliferation, and abnormal tumor blood vessels. Hypoxia leads to resistance to both radio- and chemotherapy and a predisposition to tumor metastases. Under hypoxia, sequestosome 1 (SQSTM1/p62), a multifunctional stress-inducible protein involved in various cellular processes, such as autophagy, is down-regulated. The hypoxic depletion of p62 is mediated by autophagic degradation. We herein demonstrated that hypoxia down-regulated p62 in the hepatoma cell line Hep3B at the transcriptional and post-translational levels. At the transcriptional level, hypoxia down-regulated p62 mRNA by inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2). The overexpression of Nrf2 and knockdown of Siah2, a negative regulator of Nrf2 under hypoxia, diminished the effects of hypoxia on p62 mRNA. At the post-translational level, the proteasome inhibitor MG132, but not the lysosomal inhibitors ammonium chloride and bafilomycin, prevented the hypoxic depletion of p62, suggesting the involvement of the proteasome pathway. Under hypoxia, the expression of the E3 ubiquitin ligase Parkin was up-regulated in a hypoxia-inducible factor 1α-dependent manner. Parkin ubiquitinated p62 and led to its proteasomal degradation, ensuring low levels of p62 under hypoxia. We demonstrated that the effects of Parkin on p62 required heat shock cognate 71 kDa protein (Hsc70). We also showed that the overexpression of Nrf2 and knockdown of Parkin or Hsc70 induced the accumulation of p62 and reduced the viability of cells under hypoxia. We concluded that a decrease in p62, which involves regulation at the transcriptional and post-translational levels, is critical for cell survival under hypoxia. The present results show the potential of targeting Nrf2/Parkin-Hsc70-p62 as a novel strategy to eradicate hypoxic solid tumors.

DOI: https://doi.org/10.1038/s41598-022-25784-0

Comput Biol Med. 2022 Nov 25. pii: S0010-4825(22)01055-1. [Epub ahead of print]152 106347

Omics-based identification of an NRF2-related auranofin resistance signature in cancer: Insights into drug repurposing.

Marcelo Falchetti, Marina Delgobo, Helena Zancanaro, Karoline Almeida, Raquel Nascimento das Neves, Barbara Dos Santos, Natália Marcéli Stefanes, Alexander Bishop, Maria Cláudia Santos-Silva, Alfeu Zanotto-Filho.

Auranofin is a thioredoxin reductase-1 inhibitor originally approved for the treatment of rheumatoid arthritis. Recently, auranofin has been repurposed as an anticancer drug, with pharmacological activity reported in multiple cancer types. In this study, we characterized transcriptional and genetic alterations associated with auranofin response in cancer. By integrating data from an auranofin cytotoxicity screen with transcriptome profiling of lung cancer cell lines, we identified an auranofin resistance signature comprising 29 genes, most of which are classical targets of the transcription factor NRF2, such as genes involved in glutathione metabolism (GCLC, GSR, SLC7A11) and thioredoxin system (TXN, TXNRD1). Pan-cancer analysis revealed that mutations in NRF2 pathway genes, namely KEAP1 and NFE2L2, are strongly associated with overexpression of the auranofin resistance gene set. By clustering cancer types based on auranofin resistance signature expression, hepatocellular carcinoma, and a subset of non-small cell lung cancer, head-neck squamous cell carcinoma, and esophageal cancer carrying NFE2L2/KEAP1 mutations were predicted resistant, whereas leukemia, lymphoma, and multiple myeloma were predicted sensitive to auranofin. Cell viability assays in a panel of 20 cancer cell lines confirmed the augmented sensitivity of hematological cancers to auranofin; an effect associated with dependence upon glutathione and decreased expression of NRF2 target genes involved in GSH synthesis and recycling (GCLC, GCLM and GSR) in these cancer types. In summary, the omics-based identification of sensitive/resistant cancers and genetic alterations associated with these phenotypes may guide an appropriate repurposing of auranofin in cancer therapy.

Keywords: Auranofin; Gene signature; KEAP1 mutation; NRF2 pathway; Pan-cancer; Sensitivity

DOI: https://doi.org/10.1016/j.compbiomed.2022.106347