The influence of the BRAF V600E mutation in thyroid cancer cell lines on the anticancer effects of 5-aminoimidazole-4-carboxamide-ribonucleoside

Abstract

5-Aminoimidazole-4-carboxamide-ribonucleoside (AICAR) is an activator of 50 -AMP-activated protein kinase (AMPK), which plays a role in the maintenance of cellular energy homeostasis. Activated AMPK inhibits the protein kinase mechanistic target of rapamycin, thereby reducing the extent of protein translation and suppressing both cell growth and cell cycle entry. Recent reports indicate that AMPKmediated growth inhibition is achieved via an action of the RAF-MEK-ERK mitogen-activated protein kinase pathway in melanoma cells harboring the V600E mutant form of the BRAF oncogene. In this study, we investigated the anticancer efficacy of AICAR by measuring its effects on proliferation, apoptosis, and cell cycle progression of BRAF wild-type and V600E-mutant thyroid cancer cell lines. We also explored the mechanism underlying these effects.AICAR inhibited the proliferation of BRAF V600E-mutant thyroid cancer cell lines more strongly than was the case with wild-type cell lines. The suppressive effect of AICAR on cell proliferation was associated with increased S-phase cell cycle arrest and apoptosis. Interestingly, AICAR suppressed phosphorylation of ERK and p70S6K in BRAF V600E-mutant thyroid cancer cells, but rather increased phosphorylation in wild-type cells. Together, the results indicate that AICAR-induced AMPK activation in BRAF V600E-mutant thyroid cancer cell lines resulted in increases in apoptosis and S-phase arrest via downregulation of ERK and p70S6K activity. Thus, regulation of AMPK activity may be potentially useful as a therapy for thyroid cancer if the cancer harbors a BRAF V600E mutation.

Involvement of AMP-activated protein kinase in mediating pyrrolo-1,5-benzoxazepine–induced apoptosis in neuroblastoma cells

“…5). Previous studies have reported transient effects on p70 S6 kinase activation and inactivation [34,35].…”

Energy Restriction: Stepping Stones Towards Cancer Therapy

“…Aminoimidazole carboxamide ribonucleotide (AICAR), another widely used AMPK activator, has been extensively studied in many cancer types [10]. In addition to activating AMPK, AICAR increases S-phase cell-cycle arrest and apoptosis, thereby suppressing cell proliferation [10].…”

“…In addition to activating AMPK, AICAR increases S-phase cell-cycle arrest and apoptosis, thereby suppressing cell proliferation [10].…”

“…Resveratrol activates AMPK secondary to inducing SIRT1 expression via elevation of the cellular NAD + /NADH ratio. Studies utilizing melanoma cells found that AMPK-mediated growth inhibition was achieved via inactivation of the RAF-MEK-ERK mitogen-activated protein kinase pathway [10].…”

The effect of 5-aminoimidazole-4-carboxamide-ribonucleoside was mediated by p38 mitogen activated protein kinase signaling pathway in FRO thyroid cancer cells

“…Activating AMPK inhibits the proliferation and growth of various cancer cells [1,2,3]. Some studies have demonstrated that the antitumor properties of 5-aminoimidazole-4-carboxamide-ribonucleotide (AICAR), a strong AMPK activator, are mediated by genetic mutations or are regulated in a cell-type specific manner [4,5,6]. …”