Abstract
Hepatocellular carcinoma (HCC) is a highly malignant human cancer that has increasing mortality rates worldwide. Because CD133+ cells control tumor maintenance and progression, compounds that target CD133+ cancer cells could be effective in combating HCC. We found that the administration of chromenopyrimidinone (CPO) significantly decreased spheroid formation and the number of CD133+ cells in mixed HCC cell populations. CPO not only significantly inhibited cell proliferation in HCC cells exhibiting different CD133 expression levels, but also effectively induced apoptosis and increased the expression of LC3-II in HCC cells. CPO also exhibits in vivo therapeutic efficiency in HCC. Specifically, CPO suppressed the expression of CD133 by altering the subcellular localization of CD133 from the membrane to lysosomes in CD133+ HCC cells. Moreover, CPO treatment induced point mutations in the ADRB1, APOB, EGR2, and UBE2C genes and inhibited the expression of these proteins in HCC and the expression of UBE2C is particularly controlled by CD133 expression among those four proteins in HCC. Our results suggested that CPO may suppress stemness and malignancies in vivo and in vitro by decreasing CD133 and UBE2C expression in CD133+ HCC. Our study provides evidence that CPO could act as a novel therapeutic agent for the effective treatment of CD133+ HCC.
Highlights
Hepatocellular carcinoma (HCC) is the seventh most common malignant tumor and the third leading cause of mortality worldwide [1,2,3,4]
We identified the compound, chromenopyrimidinone (CPO), which inhibited the activity of the AFP+ /CD133+ cell population and the proliferation of AFP+ /CD133− cells without damaging hepatocytes in mixed HCC cell populations (Figure 1A)
Our results found that CPO restricted the proliferation of HCC cells by inhibiting UBE2C, and controlled lipid metabolism-related proteins such as ADRB1, APOB, and EGR2
Summary
Hepatocellular carcinoma (HCC) is the seventh most common malignant tumor and the third leading cause of mortality worldwide [1,2,3,4]. HCCs are mainly resistant to common chemotherapeutic agents, and HCC patients typically have poor tolerance of systemic chemotherapy due to underlying liver dysfunction. There is no standard therapy for HCC at present. The cumulative 3-year relapse rate after liver resection is about 80%, and relapse after operation is associated with a high mortality rate [5]. A highly efficacious drug that targets the liver and induces fewer side effects would fill up a critical need in liver cancer drug discovery.
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