Regulation Of The Ras-MAPK Pathway By DUB Inhibitor In Tumor Cells

Melanoma,also known as malignant melanoma,is the most dangerous type of skin cancer.Those with a little more moles,a history of infected family members,and who have poor immune system are at greater risk,as well as high rates in the white people who live in Europe and North America,and like to exposure to UV.Surgery may remove the tumor at early stage,but it’s metastases for the recurrence is very quickly,the average survival rate is 3-11 months.BRAFV600E mutation is very frequently seen in malignant melanoma and results in constitutive activation of the RAS-independent MAPK signalling and promotes its proliferation.Vemurafinib is a very common kind of agent for the clinical therapy of BRAF-mutant tumor.However,the development of resistance remains still uncover.This study shows that the activation of a few kinds of DUBs were markedly downregulated which involved A20.Generally,almost all the proteins require post-translational modifications(PTMs)and deubiquitination has vital sense for the cell to maintain homeostasis.Aside from the MAPK/ERK and PI3K/AKT pathways,alternative studies are interested in the targeting of secondary signaling pathways involved at minor level in melanoma.Of note,NF-κB has been implicated in the proliferation of melanoma.Its blockade demonstrates in vivo reduction in melanoma tumor growth.This goes along with a substantial increase in immune response following immunotherapy(CTLA-4 or PD-1).However,the inhibition of cancer growth through the restauration of senescence is still at a very early stage of development.Likewise,The inhibition of the signal transducer and activator of transcription 3(STAT3)protein succeeds in inhibiting cell growth in cells resistant to vemurafenib.Another new study shows that,loss of stromal antigen 2(STAG2)or STAG3,which encode subunits of the cohesin complex,inhibited CCCTC-binding-factor-mediated expression of dual specificity phosphatase 6(DUSP6),leading to reactivation of MAPK signaling.IL-2(Proleukin)was the first new therapy approved(1990 Europe,1992 USA)for the treatment of metastatic melanoma in 20 years,and now with the development of biology and medical,therapeutic strategies are more complex and diverse.The rate of survival is markedly upregulated from chemotherapy to target therapy,from surgery to drugs and immunotherapy.However,the resistance to target drugs and the poor immune response will be a long problems waiting for addressing.Deubiquitin enzymes(DUBs)reverse the ubiquitination or ubiquitin-like modification of target proteinsIn ubiquitin-proteasome system.Nearly 100 putative DUBs are encoded by the human genome and they belong to five different families.Four families,the ubiquitin C-terminal hydrolases(UCH),the ubiquitin specific protease(USP/UBP),the ovarian tumor(OTU),the Josephin domain are papain-like cysteine proteases.The fifth family belongs to the JAB1/MPN/Mov34 metalloenzyme(JAMM)domain zinc-dependent metalloprotease family.Several earlier reviews specifically discuss the mutation and the abnormal expression of DUBs in Neurodegenerative disease and tumor.However,it’s hard to design the drug for DUBs on account of their similar structure.In my study,pan DUBs inhibitor PR-619 could upregulate the RAS-independent MAPK signaling in a short time in Melanoma A375 cell line.However the inhibition by Trametinib(MEK1/2 inhibitor)and PD-184352(MEK1/2 inhibitor)as well as PLX-4032(BRAFV600E inhibitor)couldn’t be reactivate by PR-619.Unexpected,PR-619 partly reactivate the inhibition from PLX-4720(RAF inhibitor).In contrast,we find that some DUBs keep in low activity in A375-PLX-4032-resistant cell line.Instant transfection assay shows that A20 could stabilize BRAF,CRAF.In conclusion,PR-619 could upregulate the RAS-independent MAPK signaling.PR-619 has a negative effect on A20 and result in the unsteadiness of BRAF,CRAF.Finally,my findings are meaningful to the clinical treatment for the melanoma.