RESUMEN
The clinical benefit of tyrosine kinase inhibitors (TKIs)-based systemic therapy for advanced hepatocellular carcinoma (HCC) is limited due to drug resistance. Here, we uncover that lipid metabolism reprogramming mediated by unconventional prefoldin RPB5 interactor (URI) endows HCC with resistance to TKIs-induced ferroptosis. Mechanistically, URI directly interacts with TRIM28 and promotes p53 ubiquitination and degradation in a TRIM28-MDM2 dependent manner. Importantly, p53 binds to the promoter of stearoyl-CoA desaturase 1 (SCD1) and represses its transcription. High expression of URI is correlated with high level of SCD1 and their synergetic expression predicts poor prognosis and TKIs resistance in HCC. The combination of SCD1 inhibitor aramchol and deuterated sorafenib derivative donafenib displays promising anti-tumor effects in p53-wild type HCC patient-derived organoids and xenografted tumors. This combination therapy has potential clinical benefits for the patients with advanced HCC who have wild-type p53 and high levels of URI/SCD1.
Asunto(s)
Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Metabolismo de los Lípidos , Factores de Transcripción/metabolismoRESUMEN
The five-year survival rate of hepatocellular carcinoma (HCC) remains unsatisfactory. This reflects, in part, the paucity of effective methods that allow the target-specific diagnosis and therapy of HCC. Here, we report a strategy based on engineered human serum albumin (HSA) that permits the HCC-targeted delivery of diagnostic and therapeutic agents. Covalent cysteine conjugation combined with the exploitation of host-guest chemistry was used to effect the orthogonal functionalization of HSA with two functionally independent peptides. One of these peptides targets glypican-3 (GPC-3), an HCC-specific biomarker, while the second reduces macrophage phagocytosis through immune-checkpoint stimulation. This orthogonally engineered HSA proved effective for the GPC-3-targeted delivery of near-infrared fluorescent and phototherapeutic agents, thus permitting target-specific optical visualization and photodynamic ablation of HCC in vivo. This study thus offers new insights into specificity-enhanced fluorescence-guided surgery and phototherapy of HCC through the orthogonal engineering of biocompatible proteins.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/terapia , Fototerapia/métodos , Albúminas , Albúmina Sérica Humana , Macrófagos/metabolismo , FagocitosisRESUMEN
Hepatocellular carcinoma has a poor prognosis due to its rapid development and early metastasis. In this report, we characterized the metabolic features of hepatocellular carcinoma using a nontargeted metabolic profiling strategy based on liquid chromatography-mass spectrometry. Fifty pairs of liver cancer samples and matched normal tissues were collected from patients having hepatocellular carcinoma, including tumor tissues, adjacent noncancerous tissues, and distal noncancerous tissues, and 105 metabolites were filtered and identified from the tissue metabolome. The principal metabolic alternations in HCC tumors included elevated glycolysis, gluconeogenesis, and ß-oxidation with reduced tricarboxylic acid cycle and Δ-12 desaturase. Furthermore, increased levels of glutathione and other antioxidative molecules, together with decreased levels of inflammatory-related polyunsaturated fatty acids and phospholipase A2, were observed. Differential metabolite levels in tissues were tested in 298 serum specimens from patients with chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Betaine and propionylcarnitine were confirmed to confer good diagnostic potential to distinguish hepatocellular carcinoma from chronic hepatitis and cirrhosis. External validation of cirrhosis and hepatocellular carcinoma serum specimens further showed that this combination biomarker is useful for diagnosis of hepatocellular carcinoma with a supplementary role to α-fetoprotein.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Metaboloma/genética , Adulto , Anciano , Antioxidantes/metabolismo , Betaína/metabolismo , Carcinoma Hepatocelular/genética , Carnitina/análogos & derivados , Carnitina/genética , Carnitina/metabolismo , Ciclo del Ácido Cítrico , Ácido Graso Desaturasas/genética , Ácido Graso Desaturasas/metabolismo , Ácidos Grasos Insaturados/genética , Ácidos Grasos Insaturados/metabolismo , Femenino , Gluconeogénesis , Glutatión/genética , Glutatión/metabolismo , Glucólisis , Hepatitis Crónica/genética , Hepatitis Crónica/metabolismo , Humanos , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Neoplasias Hepáticas/genética , Masculino , Metabolómica/métodos , Persona de Mediana Edad , Fosfolipasas A2/genética , Fosfolipasas A2/metabolismoRESUMEN
Ten steroidal alkaloids - cyclopamine, veratramine, jervine, 3, 15-diangyloylgermine, 3-angyloylzygadenine, 3-veratroyl zygadenine, 15-veratroylgermine, germine, veratrosine and pseudojervine - from Veratrum dahuricum, together with the ethanol extract and total alkaloids, were evaluated for their antitumor and antiplatelet activities. Cyclopamine, veratramine and germine significantly inhibited the hedgehog pathway in NIH/3T3 cells. Cyclopamine exerted a potent inhibitory effect against the growth of PANC-1 tumors in mice, with inhibition rates of 40.64%, 44.37%, 46.77% at doses of 5.0, 15.0 and 50.0 mg kg-1, respectively. Veratroylgermine was found to produce the strongest inhibition against the platelet aggregation induced by arachidonic acid, with inhibition rate of 92.0% at 100 microM.