mGPDH Deficiency leads to melanoma metastasis via induced NRF2

Abstract

Melanoma, which is also known as malignant melanoma, is among the most aggressive forms of skin cancer and has a poor cure rate due to its invasive nature. 1,2 Melanoma mostly develops from pigment-containing cells known as melanocytes and thus predominantly a disease of the skin but can also occur at mucous membranes and other sites. 3 With treatment, in the United States, the 5-year survival rate is 65% among

The dual role of Nrf2 in melanoma: a systematic review

“…There is evidence that Nrf2 activation enhances cancer cell metastasis in melanoma, suggesting that Nrf2 has an onco-promoter role [ 34 , 47 , 59 ]. In fact, as long as the cell is intact, Nrf2 and its lower genes try to save the cell from becoming cancerous by reducing oxidative stress.…”

“…Li et al showed that in A375 melanoma cells, knocking down mGPDH activates the Nrf2 pathway, causing melanoma cell metastasis, whereas co-inhibiting Nrf2 prevents melanoma cell metastasis in vivo and in vitro. These findings show that via inhibiting the Nrf2 signaling pathway, mGDPH suppresses melanoma cell motility and invasion [ 47 ]. P62, an autophagy-degrading factor, is overexpressed in malignant and metastatic melanomas regardless of BRAF/NRAS mutant status.…”

“…These findings support the pharmacological use of Nrf2 inhibitors such as ML385 and brusatol to avoid distant melanoma spread and treat metastatic melanomas. Although these drugs have drawbacks, they are effective [ 26 , 41 , 47 ].…”

“… mGPDH deficient cells are able to activate the Nrf2 signaling pathway, leading to melanoma progression and metastasis. [ 47 ] Liao et al, 2021 Normal skin cell line PIG1, melanoma cell lines: A375, G-361, HS1-CLS, MEL-CLS1-4, IGR-1, MEWO, NIS-G, WS1-CLS, and MML1 miR-130b-3p activates the Nrf2/HO-1 signaling pathway by inhibiting DKK1 expression in melanoma, leading to reduced melanoma cell ferroptosis. The expression of miR-130b-3p reinforces activation of the Nrf2/HO-1 pathway followed by DKK1 suppression.…”

NRF2-directed PRPS1 upregulation to promote the progression and metastasis of melanoma

“…Intermittent hypoxia promoted melanoma lung metastasis through oxidative stress in a mouse model of obstructive sleep apnea ( 46 ). Mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) inhibits melanoma migration, and invasion by suppressing NRF2 and downstream oxidative signals ( 47 ). Our study demonstrates for the first time that NRF2, as a transcription factor, can regulate the transcription of PRPS1, an important enzyme in nucleotide metabolism.…”