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 E (PGE) 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) at concentrations of 1 mmol/L and 20 μmol/L, respectively. ASA-mediated inhibition of cell migration and pigmentation was rescued by exogenous PGE 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 PGE 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 PGE in plasma and tumors and increased phosphorylated AMPK in tumors. We conclude that ASA inhibits colony formation, cell motility, and pigmentation through suppression of PGE and activation of AMPK and reduces growth of some melanoma tumors This preclinical model could be used for further tumor and biomarker studies to support future melanoma chemoprevention trials in humans..

Overcoming cancer therapeutic bottleneck by drug repurposing

“…401,402 Subsequently, aspirin was demonstrated to kill melanoma, prostate, ovarian and other cancers by inhibition of PGE2 expression. [403][404][405][406] Aspirin was also reported to mediate tumor-promoting inflammation in a COX independent manner, mainly by regulating the NF-κB signaling pathway, which was initially shown as a key event relating to chronic inflammation and increased cancer risk. 407 Zhang et al showed that some aspirin-based drugs exerted anticancer activity in colon and pancreatic cancer cells by inducing ANXA1, which could prevent NF-κB binding to DNA leading to increased apoptosis and decreased proliferation.…”

Targeting Mitochondria in Melanoma

“…Melanogenesis, a multistep and highly regulated pathway, can switch metabolism of cells from OXPHOS to anaerobic glycolysis [ 27 , 28 , 58 ] and increase mitochondrial mass [ 59 ]. For the A375 and WM3311 melanoma cell lines comparable melanin levels have been reported [ 60 , 61 ]. Thus, the melanin content of these two cell lines cannot explain differences seen in OXPHOS activity, respiration, and glycolytic activity ( Figure 1 and Figure 2 ).…”

Acetylsalicylic acid and salicylic acid present anticancer properties against melanoma by promoting nitric oxide-dependent endoplasmic reticulum stress and apoptosis

“…Indeed, we found that NO is directly involved in the process, since inhibiting eNOS in SA/ASA-treated B16F10 cells prevented the upregulation of CHOP and ATF4, and therefore preventing apoptosis trigger. The anticancer effects of ASA on melanoma have been discussed elsewhere [63][64][65][66][67][68] , but it is the first time that involvement of UPR is presented as a mechanism for this drug anticancer property. Although most of the papers dealing with implanted tumor cells in mice use immune-compromised animals, here we opted to use wild-type immune-competent C57BL6/J mice since B16F10 cells are from the same animal origin and would not be rejected by the mice.…”