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Working model. In normal ciliated cholangiocytes, ligand-induced activated EGFR translocates to the primary cilium, where it is then degraded via a mechanism involving the E3 ubiquitin ligase CBL.
The pathologically induced loss or dysfunction of cilia forbids the EGFR ciliary translocation, avoiding the receptor degradation, and enhancing EGFR signaling in ciliary- defective cells like PLD and CCA.
in tumors and kidney and liver polycystic cells. But why this abnormal activity occurs remains understudied. In this project, we found that the upregulated EGFR-MEK-ERK signaling axis and elevated EGF sensitivity in ciliary- defective cholangiocytes are related to the inability of EGFR to migrate to primary cilia. We also found that ligand-mediated activated EGFR migration to the cilia is needed for proper receptor clearance and signal termination (Figure 1). Our study reveals a cellular mechanism for the sustained
EGFR signaling observed in polycystic liver diseases and cholangiocarcinoma and provides novel insights for potential therapeutic treatments. This project is now funded by a National Institutes of Health grant.
Short Chain Fatty Acid, Butyrate, Induces Cilia Formation and Potentiates the Effects of HDAC6 Inhibitors in Cholangiocarcinoma Cells.
Cholangiocarcinoma (CCA), or bile duct cancer, is a deadly form of liver cancer with limited therapeutic approaches. The pathogenesis of CCA involves the loss of primary cilia in cholangiocytes by a mecha- nism involving increased expression of deacetylases like HDAC6 and SIRT1. Therefore, cilia restoration may represent an alternative and novel therapeutic approach against CCA. The short-chain fatty acid butyrate is a bacterial byproduct from the fermen- tation of dietary fibers in the intestine and has been shown to inhibit SIRT1, showing antitumor effects on various cancers, among other functions. In this
work, we investigated the role of butyrate on CCA cells proliferation and migration, and evaluated the synergistic effects with specific HDAC6 inhibition. When CCA cells, including HuCCT1 and KMCH, were treated with butyrate, the cilia formation and acetylat- ed-tubulin levels were increased, while no significant effects were observed in normal human cholangio- cytes. Butyrate treatment also depicted reduced cell proliferation in HuCCT1 and KMCH cells but, on the other hand, it affected cell growth of the normal chol- angiocytes only at high concentrations. In HuCCT1 cells, spheroid formation and cell migration were also halted by butyrate treatment. Furthermore, we found that butyrate augmented the previously described effects of HDAC6 inhibitors that we discovered on CCA cells proliferation and migration by reducing
the expression of CD44, cyclin D1, PCNA, Zeb1, and Vimentin. In summary, butyrate targets cancer cell growth and migration, and enhances the anti-cancer effects of HDAC6 inhibitors in CCA cells, suggesting that butyrate may have therapeutic effects in CCA and other ciliopathies.
ORCID iD: https://orcid.org/0000-0002-1753-3634
PUBLICATION HIGHTLIGHTS:
• Pant, K., Richard, S., Peixoto, E., Yin, J., Seelig, D. M., Carotenuto, P., Salati, M., Franco, B., Roberts, L. R., & Gradilone, S. A. (2023). The NAMPT Inhibitor FK866 in Combination with Cisplatin Reduces Cholangiocarcinoma Cells Growth. Cells, 12(5), 12.
• Pant, K., & Gradilone, S. A. (2022). Hepatobiliary Cancers: Progress in Diagnosis, Pathogenesis, and Treatment. Technology in Cancer Research and Treatment, 21, 15330338221097203.
• Calvisi, D. F., Boulter, L., Vaquero, J., Saborowski, A., Fabris, L., Rodrigues, P. M. ... Gradilone, S. A., CCA Model Consortium ... Fouassier, L. (2023). Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance. Nat Rev Gastroenterol Hepatol, 20(7), 462-480.