monensin and Thyroid-Neoplasms

The clinical management of anaplastic thyroid cancer (ATC) remains challenging, and novel treatment methods are needed. Monensin is a carboxyl polyether ionophore that potently inhibits the growth of various cancer types. Our current work investigates whether monensin has selective anti-ATC activity and systematically explores its underlying mechanisms.. Proliferation and apoptosis assays were performed using a panel of thyroid cancer cell lines. Mitochondrial biogenesis profiles, ATP levels, oxidative stress, AMPK, and mTOR were examined in these cells after monensin treatment.. Monensin is effective in inhibiting proliferation and inducing apoptosis in a number of thyroid cancer cell lines. The results are consistent across cell lines of varying cellular origins and genetic mutations. Compared to other thyroid cancer cell types, ATC cell lines are the most sensitive to monensin. Of note, monensin used at our experimental concentration affects less of normal cells. Mechanistic studies reveal that monensin acts on ATC cells by disrupting mitochondrial function, inducing oxidative stress and damage, and AMPK activation-induced mTOR inhibition. We further show that mitochondrial respiration is a critical target for monensin in ATC cells.. Our pre-clinical findings demonstrate the selective anti-ATC activities of monensin. This is supported by increasing evidence that monensin can be repurposed as a potential anti-cancer drug.

Topics: AMP-Activated Protein Kinases; Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Mitochondria; Monensin; Respiration; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; TOR Serine-Threonine Kinases

A rat medullary thyroid carcinoma cell line, CA-77, was shown to express the cholecystokinin (CCK) gene. Measurements using a library of sequence-specific radioimmunoassays before and after enzymic treatment of extracts and chromatographic fractions showed that the cells contained 1.0 pmol of alpha-carboxyamidated cholecystokinins/10(6) cells, 0.4 pmol of glycine-extended intermediates/10(6) cells and 1.0 pmol of further C-terminal-extended pro-CCK/10(6) cells. Gel chromatography and reverse-phase h.p.l.c. revealed both sulphated and nonsulphated CCK-8 in the cells. The growth medium contained in addition alpha-amidated CCK-33, glycine-extended CCK-8 and pro-CCK. Exposure to 0.1 microM-dexamethasone for 6 days increased the cellular content and secretion of all of the described CCK peptides by 2-3-fold. The increase was first noted after 3 days of treatment. Monensin inhibited the synthesis of alpha-carboxyamidated CCK and the secretion of all of the CCK forms measured. Colchicine at a low concentration (0.2 mumol/l) apparently increased the synthesis and secretion of alpha-carboxyamidated CCK, whereas higher concentrations inhibited CCK synthesis. Finally, chloroquine inhibited the alpha-carboxyamidation of CCK. We conclude that the CA-77 cell line is a useful tool for studies of the expression and post-translational processing of pro-CCK.

Topics: Animals; Carcinoma; Chloroquine; Cholecystokinin; Chromatography, Gel; Colchicine; Dexamethasone; Gene Expression; Glycine; Monensin; Peptide Fragments; Protein Precursors; Protein Processing, Post-Translational; Rats; Sincalide; Sulfates; Thyroid Neoplasms; Tumor Cells, Cultured