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Dual effects of acetylsalicylic acid on ERK signaling and Mitf transcription lead to inhibition of melanogenesis

Significance Statement

Non-steroidal anti-inflammatory drugs (NSAIDs) are known to act by directly suppressing the activity of cyclooxygenase, the key enzyme catalyzing the biosynthesis of prostaglandin, which induce inflammation.  Therefore, NSAIDs are usually used for treat pain, inflammation, and fever.  Acetylsalicylic acid (Aspirin) is the most prominent NSAIDs and it is available over-the-counter all over the world.  Also, aspirin has been shown to be effective as an antiplatelet drug in preventing heart attacks, stroke, and cerebral thrombosis.

Skin pigmentation results from melanin synthesis by melanocytes and is caused greater by exposure to UV radiation.  In melanin synthesis, there is a crucial enzyme called tyrosinase that catalyzes chemical reaction: amino acid tyrosine to melanin.  Therefore, mutation of the tyrosinase gene causes albinism.

In this study, we investigate the anti-melanogenic effect of aspirin on aspects of the regulation of melanogenic genes and intracellular pathways.  We focused on microphthalmia-associated transcription factor (Mitf) that is an important factor of melanin synthesis.  Once activated, Mitf promotes gene transcription by binding the promoter region of tyrosinase gene.  Interestingly, aspirin inhibited Mitf gene at the transcriptional level.  The fact that down-regulation of Mitf imply that aspirin depresses the tyrosinase gene and subsequent inhibition of melanogenesis.  Furthermore, we investigate the effect of aspirin on the extracellular signal regulated kinase (ERK) pathway.  ERK plays an important role in cellular processes such as survival, proliferation, cell cycle progression and melanin synthesis.  Activated ERK can phosphorylate Mitf, which causes degradation of Mitf, and this process also brings about inhibition of melanin synthesis.  Surprisingly, our result demonstrated that aspirin activated the ERK and it is also a leading cause of inhibition of melanogenesis.  Taken together, our results suggest that aspirin can inhibit melanin synthesis that is caused by both inhibition of Mitf gene expression and ERK activation.

Dual effects of acetylsalicylic acid on ERK signaling and Mitf transcription lead to inhibition of melanogenesis. Global Medical Discovery

About The Author

Kazuomi Sato, Ph.D.

Laboratory of Biochemistry, Department of Life Science, Tamagawa University

2009: Received his Ph.D. in Agriculture at Gifu University (Gifu, Japan)

2009-2013: Assistant Professor, Tamagawa University (Tokyo, Japan)

2014-present:  Associate Professor, Tamagawa University (Tokyo, Japan)

Research interests: Regulation of melanin synthesis, Enzyme kinetics, Mechanism of cell death.  

Journal Reference

Nishio T1, Usami M2, Awaji M2, Shinohara S2, Sato K3,4.
Show Affiliations
  1. Graduate School of Agriculture, Tamagawa University, 6-1-1 Tamagawa-gakuen, Machida, Tokyo, 194-8610, Japan.
  2. Department of Life Science, College of Agriculture, Tamagawa University, 6-1-1 Tamagawa-gakuen, Machida, Tokyo, 194-8610, Japan.
  3. Graduate School of Agriculture, Tamagawa University, 6-1-1 Tamagawa-gakuen, Machida, Tokyo, 194-8610, Japan. [email protected]
  4. Department of Life Science, College of Agriculture, Tamagawa University, 6-1-1 Tamagawa-gakuen, Machida, Tokyo, 194-8610, Japan. [email protected]

Abstract

Acetylsalicylic acid (ASA) is widely used as an analgesic/antipyretic drug. It exhibits a wide range of biological effects, including preventative effectsagainst heart attack and stroke, and the induction of apoptosis in various cancer cells. We previously found that ASA inhibits melanogenesis in B16 melanoma cells. However, the mechanisms of how ASA down-regulates melanin synthesis remain unclear. Here, we investigated the effect of ASA on melanogenic pathways, such as extracellular signal-regulated kinase (ERK) and microphthalmia-associated transcription factor (Mitf) transcription. ASA significantly inhibited melanin synthesis in a dose-dependent manner without oxidative stress and cell death. Semi-quantitative reverse transcription-polymerase chain reaction analysis showed that the inhibitory effect of ASA might be due to the inhibition of Mitf gene transcription. Interestingly, ASA also induced ERK phosphorylation. Additionally, treatment with PD98059, a specific ERK phosphorylation inhibitor, abolished the anti-melanogenic effect of ASA. These results suggest that the depigmenting effect of ASA results from down-regulation of Mitf, which is induced by both the induction of ERK phosphorylation and the inhibition of Mitf transcription.

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