p62/SQSTM1/Keap1/NRF2 Axis Reduces Cancer Cells Death-Sensitivity in Response to Zn(II)–Curcumin Complex

Garufi, Alessia; Giorno, Eugenia; Montani, Maria Saveria Gilardini; Pistritto, Giuseppa; Crispini, Alessandra; Cirone, Mara; D’Orazi, Gabriella

doi:10.3390/biom11030348

Cited by 21 publications

(14 citation statements)

References 52 publications

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“…In the cancer cell lines analyzed, Zinc–curcumin Zn (II)–curc compound can also display anticancer effects via diverse molecular mechanisms, including markedly increasing heme oxygenase-1 (HO-1) p62/SQSTM1and the Nrf2 protein levels along with its targets. It also strikingly decreases the levels of Nrf2 inhibitor, Keap1 protein.Therefore, the crosstalk between p62/SQSTM1 and Nrf2 could be therapeutically exploited to increase cancer patient response to therapies [ 31 ].…”

Section: Curcumin and Elevated Nrf2 In Preventing Cancermentioning

confidence: 99%

Nrf2 Regulation by Curcumin: Molecular Aspects for Therapeutic Prospects

et al. 2021

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Nuclear factor erythroid 2 p45-related factor (2Nrf2) is an essential leucine zipper protein (bZIP) that is primarily located in the cytoplasm under physiological conditions. Nrf2 principally modulates endogenous defense in response to oxidative stress in the brain.In this regard, Nrf2 translocates into the nucleus and heterodimerizes with the tiny Maf or Jun proteins. It then attaches to certain DNA locations in the nucleus, such as electrophile response elements (EpRE) or antioxidant response elements (ARE), to start the transcription of cytoprotective genes. Many neoplasms have been shown to have over activated Nrf2, strongly suggesting that it is responsible for tumors with a poor prognosis. Exactly like curcumin, Zinc–curcumin Zn (II)–curc compound has been shown to induce Nrf2 activation. In the cancer cell lines analyzed, Zinc–curcumin Zn (II)–curc compound can also display anticancer effects via diverse molecular mechanisms, including markedly increasing heme oxygenase-1 (HO-1) p62/SQSTM1 and the Nrf2 protein levels along with its targets. It also strikingly decreases the levels of Nrf2 inhibitor, Kelch-like ECH-associated protein 1 (Keap1) protein.As a result, the crosstalk between p62/SQSTM1 and Nrf2 could be used to improve cancer patient response to treatments. The interconnected anti-inflammatory and antioxidative properties of curcumin resulted from its modulatory effects on Nrf2 signaling pathway have been shown to improve insulin resistance. Curcumin exerts its anti-inflammatory impact through suppressing metabolic reactions and proteins such as Keap1 that provoke inflammation and oxidation. A rational amount of curcumin-activated antioxidant Nrf2 HO-1 and Nrf2-Keap1 pathways and upregulated the modifier subunit of glutamate-cysteine ligase involved in the production of the intracellular antioxidant glutathione. Enhanced expression of glutamate-cysteine ligase, a modifier subunit (GLCM), inhibited transcription of glutamate-cysteine ligase, a catalytic subunit (GCLC). A variety of in vivo, in vitro and clinical studies has been done so far to confirm the protective role of curcumin via Nrf2 regulation. This manuscript is designed to provide a comprehensive review on the molecular aspects of curcumin and its derivatives/analogs via regulation of Nrf2 regulation.

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Section: Curcumin and Elevated Nrf2 In Preventing Cancermentioning

confidence: 99%

Nrf2 Regulation by Curcumin: Molecular Aspects for Therapeutic Prospects

et al. 2021

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“…80 Importantly, studies conducted with lung cancer cells in monolayer or spheroid culture have shown that the cancer cells require NRF2 hyperactivation for their proliferation and survival. Thus, targeting NRF2 was found to efficiently inhibit lung cancer cell growth [82][83][84] or kill all cells within spheroids. 85 High levels of AhR expression in lung adenocarcinomas also are indicative of a poor prognosis 86 ; this may be due, in part, to immunosuppressive effects of AhR signaling pathways on various types of immune cells.…”

Section: Discussionmentioning

confidence: 99%

Role of NRF2 in immune modulator expression in developing lung

2021

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After birth, the alveolar epithelium is exposed to environmental pathogens and high O 2 tensions. The alveolar type II cells may protect this epithelium through surfactant production. Surfactant protein, SP-A, an immune modulator, is developmentally upregulated in fetal lung with surfactant phospholipid synthesis. Herein, we observed that the redox-regulated transcription factor, NRF2, and co-regulated C/EBPβ and PPARγ, were markedly induced during cAMP-mediated differentiation of cultured human fetal lung (HFL) epithelial cells. This occurred with enhanced expression of immune modulators, SP-A, TDO2, AhR, and NQO1. Like SP-A, cAMP induction of NRF2 was prevented when cells were exposed to hypoxia. NRF2 knockdown inhibited induction of C/EBPβ, PPARγ, and immune modulators. Binding of endogenous NRF2 to promoters of SP-A and other immune modulator genes increased during HFL cell differentiation. In mouse fetal lung (MFL), a developmental increase in Nrf2, SP-A, Tdo2, Ahr, and Nqo1 and decrease in Keap1 occurred from 14.5 to 18.5 dpc. Developmental induction of Nrf2 in MFL was associated with increased nuclear localization of NF-κB p65, a decline in p38 MAPK phosphorylation, increase in the MAPK phosphatase, DUSP1, induction of the histone acetylase, CBP, and decline in the histone deacetylase, HDAC4. Thus, together with surfactant production, type II cells protect the alveolar epithelium through increased expression of NRF2 and immune modulators to prevent inflammation and oxidative stress. Our findings further suggest that lung cancer cells have usurped this developmental pathway to promote immune tolerance and enhance survival.

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“…Indeed, the therapy with Zn (II)-curc raised the NRF2 proteins concentrations and their connections, the heme oxygenase-1 (HO-1) and p62/SQSTM1, while particularly decreased the levels of Keap1 (Kelch-like ECH-associated protein 1), which stopped the NRF2 in all the investigated malignant cell lines. The inhibition of NRF2 or p62/SQSTM1 with distinctive siRNA proved the existence of the communication channel between the two molecules, and that the easily disassemble of any molecule surged the killing of cancer cells by Zn (II)-curc, a fact that could be implemented in the future to improve the receptivity to tumors treatment by this method [70].…”

Section: Curcumin and Latest Cancer Applicationsmentioning

confidence: 97%

Latest Innovations and Nanotechnologies with Curcumin as a Nature-Inspired Photosensitizer Applied in the Photodynamic Therapy of Cancer

Ailioaie

Litscher

2021

Pharmaceutics

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In the context of the high incidence of cancer worldwide, state-of-the-art photodynamic therapy (PDT) has entered as a usual protocol of attempting to eradicate cancer as a minimally invasive procedure, along with pharmacological resources and radiation therapy. The photosensitizer (PS) excited at certain wavelengths of the applied light source, in the presence of oxygen releases several free radicals and various oxidation products with high cytotoxic potential, which will lead to cell death in irradiated cancerous tissues. Current research focuses on the potential of natural products as a superior generation of photosensitizers, which through the latest nanotechnologies target tumors better, are less toxic to neighboring tissues, but at the same time, have improved light absorption for the more aggressive and widespread forms of cancer. Curcumin incorporated into nanotechnologies has a higher intracellular absorption, a higher targeting rate, increased toxicity to tumor cells, accelerates the activity of caspases and DNA cleavage, decreases the mitochondrial activity of cancer cells, decreases their viability and proliferation, decreases angiogenesis, and finally induces apoptosis. It reduces the size of the primary tumor, reverses multidrug resistance in chemotherapy and decreases resistance to radiation therapy in neoplasms. Current research has shown that the use of PDT and nanoformulations of curcumin has a modulating effect on ROS generation, so light or laser irradiation will lead to excessive ROS growth, while nanocurcumin will reduce the activation of ROS-producing enzymes or will determine the quick removal of ROS, seemingly opposite but synergistic phenomena by inducing neoplasm apoptosis, but at the same time, accelerating the repair of nearby tissue. The latest curcumin nanoformulations have a huge potential to optimize PDT, to overcome major side effects, resistance to chemotherapy, relapses and metastases. All the studies reviewed and presented revealed great potential for the applicability of nanoformulations of curcumin and PDT in cancer therapy.

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p62/SQSTM1/Keap1/NRF2 Axis Reduces Cancer Cells Death-Sensitivity in Response to Zn(II)–Curcumin Complex

Cited by 21 publications

References 52 publications

Nrf2 Regulation by Curcumin: Molecular Aspects for Therapeutic Prospects

Nrf2 Regulation by Curcumin: Molecular Aspects for Therapeutic Prospects

Role of NRF2 in immune modulator expression in developing lung

Latest Innovations and Nanotechnologies with Curcumin as a Nature-Inspired Photosensitizer Applied in the Photodynamic Therapy of Cancer

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