Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis

Abstract

The incidence of melanoma is increasing over the years with a still poor prognosis and the lack of a cure able to guarantee an adequate survival of patients. Although the new immuno-based coupled to target therapeutic strategy is encouraging, the appearance of targeted/cross-resistance and/or side effects such as autoimmune disorders could limit its clinical use. Alternative therapeutic strategies are therefore urgently needed to efficiently kill melanoma cells. Ferroptosis induction and execution were evaluated in metastasis-derived wild-type and oncogenic BRAF melanoma cells, and the process responsible for the resistance has been dissected at molecular level. Although efficiently induced in all cells, in an oncogenic BRAF- and ER stress-independent way, most cells were resistant to ferroptosis execution. At molecular level we found that: resistant cells efficiently activate NRF2 which in turn upregulates the early ferroptotic marker CHAC1, in an ER stress-independent manner, and the aldo-keto reductases AKR1C1 ÷ 3 which degrades the 12/15-LOX-generated lipid peroxides thus resulting in ferroptotic cell death resistance. However, inhibiting AKRs activity/expression completely resensitizes resistant melanoma cells to ferroptosis execution. Finally, we found that the ferroptotic susceptibility associated with the differentiation of melanoma cells cannot be applied to metastatic-derived cells, due to the EMT-associated gene expression reprogramming process. However, we identified SCL7A11 as a valuable marker to predict the susceptibility of metastatic melanoma cells to ferroptosis. Our results identify the use of pro-ferroptotic drugs coupled to AKRs inhibitors as a new valuable strategy to efficiently kill human skin melanoma cells.

Proteomic analysis links alterations of bioenergetics, mitochondria-ER interactions and proteostasis in hippocampal astrocytes from 3xTg-AD mice

“…Primer sequences are available in Supplementary Table 1. Gapdh mRNA level was used as an internal control and results were expressed as previously described 56 .…”

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

“…It has been shown that ferroptosis-resistant cells upregulated NRF-2, which induced expression of an early ferroptotic marker glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1), and the aldo-keto reductases (AKRs) such as AKR1C1, AKR1C2, and AKR1C3 to degrade the lipid peroxides and prevent from ferroptotic cell death. Inhibition of AKR activity sensitized melanoma cells to ferroptosis confirming the role of these enzymes in prevention of ferroptosis induction [189]. In addition, NRF-2 has been implicated in UV-induced expression of PD-L1 in melanoma.…”

“…It has been hypothesized that chemosensitivity of OXPHOS high cancer cells could rely on ROS accumulation and might be potentially executed by induction of ferroptosis [188]. This suggests that a metabolic switch induced by BRAFi can sensitize melanoma cells to ferroptosis-inducing agents, and SCL7A11 has been suggested as a marker of the susceptibility of metastatic melanoma cells to ferroptosis [189]. In line with this, acute treatment with vemurafenib or trametinib reduced transcript level of SLC7A11 in BRAF V600E melanoma cells [190].…”

“…Enhanced activity of NRF-2 in melanoma was connected to genetic alterations in KEAP1, and was responsible for intrinsic resistance of melanoma cells to cisplatin and dacarbazine [204]. In a recent study, the role of NRF-2 has been more extensively investigated in melanoma cells resistant to ferroptosis [189]. It has been shown that ferroptosis-resistant cells upregulated NRF-2, which induced expression of an early ferroptotic marker glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1), and the aldo-keto reductases (AKRs) such as AKR1C1, AKR1C2, and AKR1C3 to degrade the lipid peroxides and prevent from ferroptotic cell death.…”

Effective Synergy of Sorafenib and Nutrient Shortage in Inducing Melanoma Cell Death through Energy Stress

“…Our results highlighted an early activation of caspases, key mediators of the apoptotic program and responsible for PARP cleavage, in both cell lines but restricted to the combined SOR + STV regimen (Figure 2A, upper panels). The expected lower sensitivity of SK Mel 28 cells compared to CHL-1 is also evident, due to the presence of oncogenic BRAF V600E conferring less sensitivity to apoptotic stimuli [8,[29][30][31], evidenced by a less pronounced PARP cleavage efficiency at both 4 and 6 h post treatment compared to CHL-1. The involvement of the apoptotic pathway is also highlighted by the dramatic Mcl-1 downregulation in both cell lines exposed to SOR + STV (Figure 2A, middle/bottom panels), compared to control or each individual treatment (SOR or STV), both known to affect Mcl-1 expression [32][33][34][35].…”