Targeting the Cholecystokinin Receptor: A Novel Approach for Treatment and Prevention of Hepatocellular Cancer

Abstract

Hepatocellular carcinoma (HCC) is the fastest growing cancer worldwide in part due to the obesity epidemic and fatty liver disease, particularly nonalcoholic steatohepatitis (NASH). Chronic inflammation with the release of cytokines and chemokines with activation of hepatic stellate cells results in changes of the liver extracellular matrix (ECM) that predisposes to the development of HCC. Blood levels of the gastrointestinal peptide cholecystokinin (CCK) are increased in humans and mice consuming a high-fat diet. We found that the CCK-B receptor (CCK-BR) expression increased in the livers of mice with NASH. Treatment of mice with a CCK-BR antagonist, proglumide, prevented NASH, lowered hepatic inflammatory cytokines and chemokines, reduced oxidative stress, decreased F4/80+ hepatic macrophages, and prevented HCC. CCK-AR and CCK-BR expression was increased in both murine and human HCC cell lines compared with that of normal liver, and CCK stimulated the growth of wild-type and CCK-A receptor knockout HCC cells in vitro, but not CCK-BR knockout cells suggesting that the CCK-BR mediates proliferation. Proglumide therapy significantly reduced growth by 70% and 73% in mice bearing Dt81Hepa1–6 or in RIL-75 HCC tumors, respectively. IHC of a human liver tissue array with a selective CCK-BR antibody revealed staining of human HCC and no staining in normal liver. Prevention Relevance: This investigation demonstrates the role of the gastrointestinal peptide cholecystokinin (CCK) in hepatocellular carcinoma (HCC) and how CCK-BR blockade reverses the premalignant state of the hepatic extracellular matrix hence, rendering it less susceptible to the development of HCC. Thereby, CCK-BR blockade is a novel approach for the prevention/treatment of HCC.

Proglumide Reverses Nonalcoholic Steatohepatitis by Interaction with the Farnesoid X Receptor and Altering the Microbiome

“…We have previously shown that proglumide therapy could decrease fibrosis by preventing stellate cell activation in the mouse liver [21] and in the pancreas microenvironment [61]; therefore, we assume that the anti-fibrotic effect seen in the livers of the CDE-fed mice treated with proglumide in this investigation was related to the blockade of the CCK receptor on mouse stellate cells in the liver. The reduction in hepatic inflammation observed in the CDE/Prog-treated mice of this study may be due to proglumide's action on reducing inflammatory cytokines and chemokines as previously described [27]. The mechanism by which proglumide decreases cytokines and inflammation is unknown; however, CCK receptors and chemokine receptors are both G-protein coupled receptors (GPCRs).…”

“…This study showed that a cholecystokinin receptor inhibitor, proglumide, decreases the histologic and biochemical development of NASH in a murine model. One mechanism of action to explain this finding was previously attributed to the interaction of proglumide at the CCK-B receptors that are increased in expression in the mouse NASH liver [27]. However, a novel finding of this investigation is that proglumide also decreases NASH by acting as a partial agonist at the farnesoid X receptor in the murine liver.…”

A Novel Purine and Uric Metabolism Signature Predicting the Prognosis of Hepatocellular Carcinoma

“…Serum levels of CCK are elevated in HCC patients, and CCK blockade is a novel approach for the prevention/treatment of HCC. ( Tucker et al, 2020 ; Gay et al, 2021 ). However, there are few studies on the relationship between TACR1 and HCC.…”

Safety and Pharmacokinetic Assessment of Oral Proglumide in Those with Hepatic Impairment

“…The cholecystokinin-B receptor (CCK-BR) is not found in normal liver tissue (mouse or human) but becomes overexpressed in NASH and HCC [ 18 ]. In fact, in [ 19 ] 35% of the mice on a NASH-inducing diet developed dysplastic nodules or HCC after 18 weeks, while none of the mice treated with a CCK-BR antagonist, proglumide, developed HCC.…”

“…In fact, in [ 19 ] 35% of the mice on a NASH-inducing diet developed dysplastic nodules or HCC after 18 weeks, while none of the mice treated with a CCK-BR antagonist, proglumide, developed HCC. Further examination of the mouse NASH livers in this study showed that treatment with the CCK receptor antagonist, proglumide, rendered the liver microenvironment less carcinogenic by decreasing fibrosis, inflammatory chemokines, and cytokines and reducing M2-polarized macrophages [ 18 ]. In fact, treatment of mice bearing HCC tumors with proglumide monotherapy resulted in a significant reduction in cancer growth compared with controls [ 18 ].…”