Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis
Mara GagliardiDiego CotellaClaudio SantoroDavide CoràNickolai A. BarlevMauro PiacentiniMarco Corazzari
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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.AbstractMutation of BRAF has been proposed to contribute to melanoma development. However, it remains unclear whether or not BRAF mutation is associated with any particular stage of melanoma progression. Tumor biopsy specimens from patients with melanoma were analyzed to determine whether the frequency of BRAF mutation in metastatic melanoma differed from primary melanoma. BRAF mutation was present in 15 of 23 (61%) patients with primary melanoma and in 7 of 12 (58%) patients with metastatic melanoma. These results suggest that BRAF mutation in melanoma is most likely to occur prior to the development of metastatic disease.
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Despite the consensus that accumulation of unfolded proteins in the endoplasmic reticulum (ER) lumen, i.e. ER stress, activates the unfolded protein response (UPR), studies under physiological and pathophysiological conditions suggest that ER stress may not always trigger the UPR, and the UPR can be activated in an ER stress-independent way. To better understand how the UPR is regulated and its relationship with ER stress requires direct detection of unfolded proteins in the ER, a method that is still lacking. Here, we report a strategy of visualizing unfolded protein accumulation in the ER lumen in living cells by employing an engineered ER stress sensor, PERK, which forms fluorescence puncta upon unfolded protein binding, in a fast and reversible way. Our reporter enables us to clarify the involvement of unfolded proteins in UPR activation under several physiological conditions and suggests that persistent unfolded protein accumulation in the ER despite UPR attenuation predicts cell death.
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Abstract The Unfolded Protein Response (UPR) is an essential cellular process activated by the accumulation of unfolded proteins within the Endoplasmic Reticulum (ER), a condition referred to as ER stress. Three ER anchored receptors, IRE1, PERK and ATF6 act as ER stress sensors monitoring the health of the ER. Upon detection of ER stress, IRE1, PERK and ATF6 initiate downstream signaling pathways collectively referred to as the UPR. The overarching aim of the UPR is to restore ER homeostasis by reducing ER stress, however if that is not possible, the UPR transitions from a pro-survival to a pro-death response. While our understanding of the key signaling pathways central to the UPR is well defined, the same is not true of the subtle signaling events that help fine tune the UPR, supporting its ability to adapt to varying amplitudes or durations of ER stress. In this study, we demonstrate cross talk between the IRE1 and PERK branches of the UPR, wherein IRE1 via XBP1s signaling helps to sustain PERK expression during prolonged ER stress. Our findings suggest cross talk between UPR branches aids adaptiveness thereby helping to support the plasticity of UPR signaling responses.
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When endoplasmic reticulum (ER) stress occurs, a collection of phylogenetically conserved signaling pathways, termed unfolded protein response (UPR) pathways, monitors the stress level in the ER and is activated to restore homeostasis. If stress is overwhelming, activation of these signaling pathways also leads to apoptosis. The initial response in the ER is fluxed into several parallel branches, i.e., IRE1, PERK, and ATF6 branch. How they coordinate in response to different ER stress levels remains largely unknown. Here, we constructed a dual-reporter system to simultaneously monitor and quantify the response of both the IRE1 and PERK branches. We found that the IRE1 and PERK branches were highly coordinated via mutual inhibition. Furthermore, IRE1 branch was more sensitive to ER stress than the PERK branch under low ER stress and IRE1 activity was attenuated under high ER stress. The differential sensitivity between the two branches arises from the interbranch inhibitor p58 IPK , rather than the intra-branch inhibitor GADD34. Our results suggested a model where cells use the antagonistic crosstalk between parallel UPR signaling pathways to fine-tune their activities in response to different ER stress levels.
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Metastatic malignant melanoma belongs to a group of cancers with high mortality. In recent years, advances in our knowledge of the pathogenesis of melanoma and the discovery of new drugs has resulted in significant progress in the treatment of metastatic malignant melanoma patients. The development of resistance to these drugs, however, remains a challenge. One way how to avoid resistance, or at least delay it, is to administer combination therapy.This case study demonstrates that combination therapy with a BRAF and a MEK inhibitor can be used to successfully treat metastatic malignant melanoma patients and suggests they should be employed in therapeutic algorithms for patients with metastatic malignant melanoma and BRAF gene mutations.
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Epidermotropic metastatic malignant melanoma can simulate a primary malignant melanoma. However, since therapeutic management can be drastically different for these two lesions, care must be taken in evaluating them. We report a woman with forty-eight metastatic lesions of malignant melanoma, twenty-two of which were removed and found on histologic examination to be epidermotropic metastatic malignant melanoma.
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Various stresses cause the accumulation of unfolded proteins in the endoplasmic reticulum (ER). To manage the state, cells have the unfolded protein responses (UPR). If the UPR is unsuccessful, ER-mediated apoptosis occurs. To date, three types of UPR, i.e. the induction of chaperones, the translation block, and ER-associated degradation (ERAD) have been reported. To sense the accumulation of unfolded proteins, the ER has IRE1, PERK, and ATF6. The pathways mediated by IRE1 and ATF6 cause the induction of chaperones. The pathway mediated by PERK causes a translation block. The induction of caspase 12, the activation of the JNK pathway, and the induction of CHOP have been reported as apoptosis caused by ER stress. The stability of the cell is based on the balance between UPR and ER-mediated apoptosis. Recently several diseases have been reported to be related to ER stress. We reported that mutant presenilin 1 causes a vulnerability to ER stress because it attenuates the activation of IRE1, PERK, and ATF6. Recent reports have also shown that Parkinson disease and polyglutamine diseases are relevant to ER stress. Therefore it is suggested that the ER stress story is the common mechanism for neurodegerative disorders.
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