Aspirin Suppresses PGE2 and Activates AMP Kinase to Inhibit Melanoma Cell Motility, Pigmentation, and Selective Tumor Growth In Vivo.

Abstract

There are conflicting epidemiologic data on whether chronic aspirin (ASA) use may reduce melanoma risk in humans. Potential anticancer effects of ASA may be mediated by its ability to suppress prostaglandin E2 (PGE2) production and activate 5'-adenosine monophosphate-activated protein kinase (AMPK). We investigated the inhibitory effects of ASA in a panel of melanoma and transformed melanocyte cell lines, and on tumor growth in a preclinical model. ASA and the COX-2 inhibitor celecoxib did not affect melanoma cell viability, but significantly reduced colony formation, cell motility, and pigmentation (melanin production) in vitro at concentrations of 1 mmol/L and 20 μmol/L, respectively. ASA-mediated inhibition of cell migration and pigmentation was rescued by exogenous PGE2 or Compound C, which inhibits AMPK activation. Levels of tyrosinase, MITF, and p-ERK were unaffected by ASA exposure. Following a single oral dose of 0.4 mg ASA to NOD/SCID mice, salicylate was detected in plasma and skin at 4 hours and PGE2 levels were reduced up to 24 hours. Some human melanoma tumors xenografted into NOD/SCID mice were sensitive to chronic daily ASA administration, exhibiting reduced growth and proliferation. ASA-treated mice bearing sensitive and resistant tumors exhibited both decreased PGE2 in plasma and tumors and increased phosphorylated AMPK in tumors. We conclude that ASA inhibits colony formation, cell motility, and pigmentation through suppression of PGE2 and activation of AMPK and reduces growth of some melanoma tumors in vivo This preclinical model could be used for further tumor and biomarker studies to support future melanoma chemoprevention trials in humans. Cancer Prev Res; 11(10); 629-42. ©2018 AACR.

• Authors: Dileep Kumar, Hafeez Rahman, Ethika Tyagi, Tong Liu, Chelsea Li, Ran Lu, David Lum, Sheri L Holmen, J Alan Maschek, James E Cox, Matthew W VanBrocklin, Douglas Grossman
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 11 Issue 10 Pg. 629-642 (10 2018) ISSN: 1940-6215 [Electronic] United States
• PMID: 30021726 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Cyclooxygenase 2 Inhibitors
• Adenylate Kinase
• Celecoxib
• Dinoprostone
• Aspirin

Topics

• Adenylate Kinase (metabolism)
• Administration, Oral
• Animals
• Aspirin (pharmacology, therapeutic use)
• Celecoxib (pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Dinoprostone (metabolism)
• Female
• Humans
• Male
• Melanoma (pathology, prevention & control)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Phosphorylation (drug effects)
• Skin Neoplasms (pathology, prevention & control)
• Skin Pigmentation (drug effects)
• Xenograft Model Antitumor Assays