Effect of Heme Oxygenase-1 on Melanoma Development in Mice—Role of Tumor-Infiltrating Immune Cells

Waś, Halina; Cichoń, Tomasz; Smolarczyk, Ryszard; Lackowska, B; Mazur-Biały, Agnieszka; Mazur, Magdalena; Szade, Agata; Dominik, Pawel K.; Mazan, Milena; Kotlinowski, Jerzy; Zebzda, Anna; Kusienicka, Anna; Kiéda, Claudine; Dulak, Józef; Józkowicz, Alicja

doi:10.3390/antiox9121223

Cited by 10 publications

(11 citation statements)

References 63 publications

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“…As previously mentioned, the role of HO-1 in cancer is quite controversial since this enzyme can behave either as an anti-tumour factor or as a pro-tumour one [56,57,89]. HO-1 hyperactivation has been widely associated with tumour progression and acquired resistance to conventional chemotherapy [90][91][92]. Intriguingly, HO-1 cellular localization seems to drive different functions.…”

Section: The Pro-tumour Role Of Nrf2mentioning

confidence: 99%

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

Emanuele

Celesia

D’Anneo

et al. 2021

IJMS

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Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known transcription factor best recognised as one of the main regulators of the oxidative stress response. Beyond playing a crucial role in cell defence by transactivating cytoprotective genes encoding antioxidant and detoxifying enzymes, Nrf2 is also implicated in a wide network regulating anti-inflammatory response and metabolic reprogramming. Such a broad spectrum of actions renders the factor a key regulator of cell fate and a strategic player in the control of cell transformation and response to viral infections. The Nrf2 protective roles in normal cells account for its anti-tumour and anti-viral functions. However, Nrf2 overstimulation often occurs in tumour cells and a complex correlation of Nrf2 with cancer initiation and progression has been widely described. Therefore, if on one hand, Nrf2 has a dual role in cancer, on the other hand, the factor seems to display a univocal function in preventing inflammation and cytokine storm that occur under viral infections, specifically in coronavirus disease 19 (COVID-19). In such a variegate context, the present review aims to dissect the roles of Nrf2 in both cancer and COVID-19, two widespread diseases that represent a cause of major concern today. In particular, the review describes the molecular aspects of Nrf2 signalling in both pathological situations and the most recent findings about the advantages of Nrf2 inhibition or activation as possible strategies for cancer and COVID-19 treatment respectively.

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Section: The Pro-tumour Role Of Nrf2mentioning

confidence: 99%

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

Emanuele

Celesia

D’Anneo

et al. 2021

IJMS

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“…HO-1 is often overexpressed in cancer cells and induced by cancer therapies [ 28 , 29 , 30 ]. In this study, we used the B16-F10 murine melanoma cells engineered to stably overexpress HO-1 together with Luc transgene ( Figure S1 ) or with GFP-Luc transgene [ 46 ]. Engineered control cells expressed reporter proteins only.…”

Section: Resultsmentioning

confidence: 99%

“…Transduced B16-F10 HO-1 Luc cells were selected using 2 μg/mL puromycin (Sigma-Aldrich, Saint Louis, MO, USA). In some experiments, we used the B16-F10 HO-1 GFP-Luc cell line that was generated in our previous study [ 46 ].…”

Section: Methodsmentioning

confidence: 99%

Heme Oxygenase-1 Has a Greater Effect on Melanoma Stem Cell Properties Than the Expression of Melanoma-Initiating Cell Markers

Kusienicka

Bukowska-Straková

Cieśla

et al. 2022

IJMS

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Melanoma-initiating cells (MICs) contribute to the tumorigenicity and heterogeneity of melanoma. MICs are identified by surface and functional markers and have been shown to display cancer stem cell (CSC) properties. However, the existence of MICs that follow the hierarchical CSC model has been questioned by studies showing that single unselected melanoma cells are highly tumorigenic in xenotransplantation assays. Herein, we characterize cells expressing MIC markers (CD20, CD24, CD133, Sca-1, ABCB1, ABCB5, ALDHhigh) in the B16-F10 murine melanoma cell line. We use flow cytometric phenotyping, single-cell sorting followed by in vitro clonogenic assays, and syngeneic in vivo serial transplantation assays to demonstrate that the expression of MIC markers does not select CSC-like cells in this cell line. Previously, our group showed that heme-degrading enzyme heme oxygenase-1 (HO-1) can be upregulated in melanoma and increase its aggressiveness. Here, we show that HO-1 activity is important for non-adherent growth of melanoma and HO-1 overexpression enhances the vasculogenic mimicry potential, which can be considered protumorigenic activity. However, HO-1 overexpression decreases clone formation in vitro and serial tumor initiation in vivo. Thus, HO-1 plays a dual role in melanoma, improving the progression of growing tumors but reducing the risk of melanoma initiation.

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“…Importantly, it has been recently shown that specific upregulation of HO-1 in tumor associated macrophages shapes the immunosuppressive tumor microenvironment [ 55 ], favoring melanoma progression, whilst inhibition of HO-1 using ZnPPIX efficiently restores immune recognition [ 56 ]. However, contrasting results on antitumor activity of immune cells overexpressing HO-1 have been also reported [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

HO-1 Limits the Efficacy of Vemurafenib/PLX4032 in BRAFV600E Mutated Melanoma Cells Adapted to Physiological Normoxia or Hypoxia

et al. 2022

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Induction of heme oxygenase 1 (HO-1) favors immune-escape in BRAFV600 melanoma cells treated with Vemurafenib/PLX4032 under standard cell culture conditions. However, the oxygen tension under standard culture conditions (~18 kPa O2) is significantly higher than the physiological oxygen levels encountered in vivo. In addition, cancer cells in vivo are often modified by hypoxia. In this study, MeOV-1 primary melanoma cells bearing the BRAFV600E mutation, were adapted to either 5 kPa O2 (physiological normoxia) or 1 kPa O2 (hypoxia) and then exposed to 10 μM PLX4032. PLX4032 abolished ERK phosphorylation, reduced Bach1 expression and increased HO-1 levels independent of pericellular O2 tension. Moreover, cell viability was significantly reduced further in cells exposed to PLX4032 plus Tin mesoporphyrin IX, a HO-1 inhibitor. Notably, our findings provide the first evidence that HO-1 inhibition in combination with PLX4032 under physiological oxygen tension and hypoxia restores and increases the expression of the NK ligands ULBP3 and B7H6 compared to cells exposed to PLX4032 alone. Interestingly, although silencing NRF2 prevented PLX4032 induction of HO-1, other NRF2 targeted genes were unaffected, highlighting a pivotal role of HO-1 in melanoma resistance and immune escape. The present findings may enhance translation and highlight the potential of the HO-1 inhibitors in the therapy of BRAFV600 melanomas.

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Effect of Heme Oxygenase-1 on Melanoma Development in Mice—Role of Tumor-Infiltrating Immune Cells

Cited by 10 publications

References 63 publications

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

Heme Oxygenase-1 Has a Greater Effect on Melanoma Stem Cell Properties Than the Expression of Melanoma-Initiating Cell Markers

HO-1 Limits the Efficacy of Vemurafenib/PLX4032 in BRAFV600E Mutated Melanoma Cells Adapted to Physiological Normoxia or Hypoxia

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