HO‐1 downregulation favors BRAF^V600 melanoma cell death induced by Vemurafenib/PLX4032 and increases NK recognition

Abstract

Heme oxygenase 1 (HO‐1) plays a pivotal role in preventing cell damage. Indeed, through the antioxidant, antiapoptotic and anti‐inflammatory properties of its metabolic products, it favors cell adaptation against different stressors. However, HO‐1 induction has also been related to the gain of resistance to therapy in different types of cancers and its involvement in cancer immune‐escape has been hypothesized. We have investigated the role of HO‐1 expression in Vemurafenib‐treated BRAFV600 melanoma cells in modulating their susceptibility to NK cell‐mediated recognition. Different cell lines, isolated in house from melanoma patients, have been exposed to 1–10 μM PLX4032, which efficiently reduced ERK phosphorylation. In three lines, Vemurafenib was able to induce only a limited decrease in cell viability, while HO‐1 expression was upregulated. HO‐1 silencing/inhibition was able to induce a further significant reduction of Vemurafenib‐treated melanoma viability. Moreover, while NK cell degranulation and killing activity were decreased upon interaction with melanoma exposed to Vemurafenib, HO‐1 silencing was able to completely restore NK cell ability to degranulate and kill. Furthermore, melanoma cell treatment with Vemurafenib downregulated the expression of ligands of NKp30 and NKG2D activating receptors, and HO‐1 silencing/inhibition was able to restore their expression. Our results indicate that HO‐1 downregulation can both improve the efficacy of Vemurafenib on melanoma cells and favor melanoma susceptibility to NK cell‐mediated recognition and killing.

Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment?

“…It is important to note that HMOX1 and its metabolic byproducts can be involved in the generation of a permissive microenvironment, which is fundamental for cancer progression. In this context, a role for HMOX1 derived bilirubin has been implicated by Di Biase et al (2016) and our group (Furfaro et al, 2019) in the progression of melanoma. Considering the role HMOX1 in reducing immune-surveillance, in favoring angiogenesis and invasiveness, it seems likely that some of these properties can be ascribed to the in loco generation of bilirubin.…”

The Diverse Roles of Heme Oxygenase-1 in Tumor Progression

“…CO has been demonstrated to suppress the activation of endothelial cells in response to cytokines in vitro and reduced their expression of key adhesion molecules P- and E-selectin, ICAM-1 and VCAM that prevented neutrophil adhesion ( 146 ) ( Figure 4 ). HO-1 activity may also suppress neutrophil ( 147 , 148 ) and natural killer (NK) cell ( 149 , 150 ) activation and effector function ( Figure 4 ). HO-1 activity has been reported to suppress NK cell activation through suppressing their expression of activatory receptors such as NKG2D, NKp46 and NKp30, as well as compromising their ability to secrete IFN-γ and TNF-α ( 149 ) ( Figure 4 ).…”

Heme oxygenase promotes B‐Raf‐dependent melanosphere formation

“…Our work adds to a growing body of evidence implicating HMOX1 in melanoma tumor growth, migration, invasion and Vemurafenib (PLX‐4032) resistance. A recent publication demonstrated that downregulation of HMOX1 improved sensitivity to the B‐Raf V600E kinase inhibitor, PLX‐4032, in human melanoma cells harboring the B‐Raf V600E mutation (Furfaro et al., 2020). As acquired resistance remains a significant problem for melanoma patients (Welsh, Rizos, Scolyer, & Long, 2016), targeting of HMOX1 may provide a means to sensitize melanomas to Vemurafenib treatment.…”