PRP4 Promotes Skin Cancer by Inhibiting Production of Melanin, Blocking Influx of Extracellular Calcium, and Remodeling Cell Actin Cytoskeleton

Pre-mRNA processing factor 4B (PRP4) has previously been shown to induce epithelial-mesenchymal transition (EMT) and drug resistance in cancer cell lines. As melanin plays an important photoprotective role in the risk of sun-induced skin cancers, we have investigated whether PRP4 can induce drug res...

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Veröffentlicht in:International journal of molecular sciences 2021-07, Vol.22 (13), p.6992
Hauptverfasser: Ahmed, Muhammad Bilal, Islam, Salman Ul, Lee, Young Sup
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description Pre-mRNA processing factor 4B (PRP4) has previously been shown to induce epithelial-mesenchymal transition (EMT) and drug resistance in cancer cell lines. As melanin plays an important photoprotective role in the risk of sun-induced skin cancers, we have investigated whether PRP4 can induce drug resistance and regulate melanin biosynthesis in a murine melanoma (B16F10) cell line. Cells were incubated with a crucial melanogenesis stimulator, alpha-melanocyte-stimulating hormone, followed by transfection with PRP4. This resulted in the inhibition of the production of melanin via the downregulation of adenylyl cyclase-cyclic adenosine 3′,5′-monophosphate (AC)–(cAMP)–tyrosinase synthesis signaling pathway. Inhibition of melanin production by PRP4 leads to the promotion of carcinogenesis and induced drug resistance in B16F10 cells. Additionally, PRP4 overexpression upregulated the expression of β-arrestin 1 and desensitized the extracellular calcium-sensing receptor (CaSR), which in turn, inhibited the influx of extracellular Ca2+ ions. The decreased influx of Ca2+ was confirmed by a decreased expression level of calmodulin. We have demonstrated that transient receptor potential cation channel subfamily C member 1 was involved in the influx of CaSR-induced Ca2+ via a decreasing level of its expression. Furthermore, PRP4 overexpression downregulated the expression of AC, decreased the synthesis of cAMP, and modulated the actin cytoskeleton by inhibiting the expression of Ras homolog family member A (RhoA). Our investigation suggests that PRP4 inhibits the production of melanin in B16F10 cells, blocks the influx of Ca2+ through desensitization of CaSR, and modulates the actin cytoskeleton through downregulating the AC–cAMP pathway; taken together, these observations collectively lead to the promotion of skin carcinogenesis.
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subjects Actin
Adenosine
Adenylate cyclase
Arrestin
Biosynthesis
Calcium (extracellular)
Calcium influx
Calcium ions
Calcium-binding protein
Calcium-sensing receptors
Calmodulin
Carcinogenesis
Carcinogens
Cell adhesion & migration
Cell cycle
Cell growth
Cyclic AMP
Cyclin-dependent kinases
Cytoskeleton
Desensitization
Drug resistance
Homology
Investigations
Kinases
Melanin
Melanocyte-stimulating hormone
Melanoma
Mesenchyme
Morphology
mRNA
mRNA processing
Mutation
Post-transcription
Proteins
RhoA protein
Signal transduction
Skin cancer
Stimulators
Transcription factors
Transfection
Tumor cell lines
Tyrosinase
title PRP4 Promotes Skin Cancer by Inhibiting Production of Melanin, Blocking Influx of Extracellular Calcium, and Remodeling Cell Actin Cytoskeleton
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