Knocking out alpha-synuclein in melanoma cells dysregulates cellular iron metabolism and suppresses tumor growth

Abstract

The protein alpha-synuclein (α-syn) is unusual because, depending on its conformation and the type of cell in which it is expressed, it is pro-death or pro-survival, triggering neurodegeneration in Parkinson’s disease and enhancing cell survival of some melanomas. To probe the function of α-syn in melanoma, we used CRISPR/Cas9 to knockout SNCA, the gene that codes for α-syn, in SK-Mel-28 melanoma cells. The SNCA-knockout clones in culture exhibited a decrease in the transferrin receptor 1 (TfR1), an increase in ferritin, an increase of reactive oxygen species and proliferated slower than control cells. These SNCA-knockout clones grafted into SCID mice grew significantly slower than the SK-Mel-28 control cells that expressed α-syn. In the excised SNCA-knockout xenografts, TfR1 decreased 3.3-fold, ferritin increased 6.2-fold, the divalent metal ion transporter 1 (DMT1) increased threefold, and the iron exporter ferroportin (FPN1) decreased twofold relative to control xenografts. The excised SNCA-KO tumors exhibited significantly more ferric iron and TUNEL staining relative to the control melanoma xenografts. Collectively, depletion of α-syn in SK-Mel-28 cells dysregulates cellular iron metabolism, especially in xenografts, yielding melanoma cells that are deficient in TfR1 and FPN1, that accumulate ferric iron and ferritin, and that undergo apoptosis relative to control cells expressing α-syn.

Linking Parkinson's Disease and Melanoma: Interplay Between α‐Synuclein and Pmel17 Amyloid Formation

“…48,70,113 Turriani et al 69 reported a basal level of SNCA expression within healthy skin tissue, which was increased in vertical growth phase and metastatic growth phase melanoma tissue, the most aggressive stages of melanoma growth and progression. In addition, work from Shekoohi et al 114 has shown that knocking out SNCA in SK-MEL 28 cells suppressed tumor growth. Does this suggest that α-syn is ubiquitously expressed in melanocytes, where it normally acts to promote cell survival but when upregulated leads to uncontrolled growth, that is, melanoma?…”

Liquid-biopsy transcriptomic profiling uncovers molecular mediators of resistance to androgen receptor signaling inhibition in lethal prostate cancer

“…Heme metabolism was the second most enriched pathway in CTCs at progression. Intriguingly, leading edge genes analysis identified key regulators of iron metabolism (SCNA, HMBS and TFRC; data not shown), which are frequently upregulated in cancer cells (Shekoohi et al, 2021). Considering that Heme metabolism pathway is found enriched exclusively in the CTC compartment and that the heme structure is an essential cofactor for enzymatic complexes of the electron transport chain and the cytochromes, we posit that this enrichment reflects augmented tumor-specific metabolic requirements at progression.…”

A Deep Learning Framework for Prediction of Clinical Drug Response of Cancer Patients and Identification of Drug Sensitivity Biomarkers using Preclinical Samples

“…α-syn is frequently expressed in various brain tumours and melanoma [42, 43] and its upregulation has been linked to aggressive phenotypes of meningiomas [44]. Moreover, loss of α-syn results in dysregulation of iron metabolism and suppression of melanoma tumour growth [45]. Oncogenic activation of synuclein contributes to the cancer development by promoting tumor cell survival via activation of JNK/caspase apoptosis pathway and ERK and by providing resistance to certain chemotherapeutic drugs [46, 47], suggesting synuclein as a new therapeutic target for future treatment to overcome resistance to certain chemotherapeutic.…”