Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent and malignant cancers with high inter- and intra-tumor heterogeneity. A central common signaling mechanism in cancer is proline-directed phosphorylation, which is further regulated by the unique proline isomerase Pin1. Pin1 is prevalently overexpressed in human cancers including ~70% of HCC, and promotes tumorigenesis by activating multiple cancer-driving pathways. However, it was challenging to evaluate the significance of targeting Pin1 in cancer treatment until the recent identification of all-trans retinoic acid (ATRA) as a Pin1 inhibitor. Here we systematically investigate functions of Pin1 and its inhibitor ATRA in the development and treatment of HCC. Pin1 knockdown potently inhibited HCC cell proliferation and tumor growth in mice. ATRA-induced Pin1 degradation inhibited the growth of HCC cells, although at a higher IC50 as compared with breast cancer cells, likely due to more active ATRA metabolism in liver cells. Indeed, inhibition of ATRA metabolism enhanced the sensitivity of HCC cells to ATRA. Moreover, slow-releasing ATRA potently and dose-dependently inhibited HCC growth in mice. Finally, chemical or genetic Pin1 ablation blocked multiple cancer-driving pathways simultaneously in HCC cells. Thus, targeting Pin1 offers a promising therapeutic approach to simultaneously stop multiple cancer-driving pathways in HCC.
Highlights
Pin[1] is prevalently overexpressed or overactivated in many cancer types[13], Pin[1] promotes cancer and cancer stem cells tumorigenesis by turning on more than 40 oncogenes/growth-promoting factors and off more than 20 tumor suppresses/growth-inhibitory factors[12]
Pin[1] physically interacts with and increases hepatitis B virus X-protein (HBx) protein stability to enhance hepatocarcinogenesis[44]. These results suggest that Pin[1] plays an important role in hepatocarcinogenesis, functioning as novel anticancer target
Since lack of Pin[1] has little effect on normal tissues and cells, as demonstrated in Pin1−/− mice and MEFs14, these results indicate that human Hepatocellular carcinoma (HCC) cells likely develop addiction to Pin[1], demonstrating a pivotal role for Pin[1] in HCC cells in vitro
Summary
Pin[1] is prevalently overexpressed or overactivated in many cancer types[13], Pin[1] promotes cancer and cancer stem cells tumorigenesis by turning on more than 40 oncogenes/growth-promoting factors and off more than 20 tumor suppresses/growth-inhibitory factors[12]. Using slow-releasing ATRA pellets to maintain constant blood drug levels, we have shown that ATRA exerts potent anticancer activity against both APL and aggressive triple negative breast cancer by inhibiting and ablating Pin[1] and thereby turning off and on numerous oncogenes and tumor suppressors, respectively, at the same time[22]. These results indicate that Pin[1] inhibitors have the unique and promising property to effectively block multiple cancer-driving pathways at once[12,22]. These results demonstrate that Pin[1] is a promising therapeutic target in HCC and provide a further rationale for developing longer half-life ATRA or more potent and specific Pin1-targeted ATRA variants for treating HCC and other cancers
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