Potent Inhibition of Macropinocytosis by Niclosamide in Cancer Cells: A Novel Mechanism for the Anticancer Efficacy for the Antihelminthic.

Abstract

Niclosamide, a drug used to treat tapeworm infection, possesses anticancer effects by interfering with multiple signaling pathways. Niclosamide also causes intracellular acidification. We have recently discovered that the amino acid transporter SLC38A5, an amino acid-dependent Na+/H+ exchanger, activates macropinocytosis in cancer cells via amino acid-induced intracellular alkalinization. Therefore, we asked whether niclosamide will block basal and SLC38A5-mediated macropinocytosis via intracellular acidification. We monitored macropinocytosis in pancreatic and breast cancer cells using TMR-dextran and the function of SLC38A5 by measuring Li+-stimulated serine uptake. The peptide transporter activity was measured by the uptake of glycylsarcosine. Treatment of the cancer cells with niclosamide caused intracellular acidification. The drug blocked basal and serine-induced macropinocytosis with differential potency, with an EC50 of ~5 μM for the former and ~0.4 μM for the latter. The increased potency for amino acid-mediated macropinocytosis is due to direct inhibition of SLC38A5 by niclosamide in addition to the ability of the drug to cause intracellular acidification. The drug also inhibited the activity of the H+-coupled peptide transporter. We conclude that niclosamide induces nutrient starvation in cancer cells by blocking macropinocytosis, SLC38A5 and the peptide transporter. These studies uncover novel, hitherto unknown, mechanisms for the anticancer efficacy of this antihelminthic.

• Authors: Souad R Sennoune, Gunadharini Dharmalingam Nandagopal, Sabarish Ramachandran, Marilyn Mathew, Sathish Sivaprakasam, Valeria Jaramillo-Martinez, Yangzom D Bhutia, Vadivel Ganapathy
• Journal: Cancers (Cancers (Basel)) Vol. 15 Issue 3 (Jan 26 2023) ISSN: 2072-6694 [Print] Switzerland
• PMID: 36765717 (Publication Type: Journal Article)