Bilirubin inhibits the anticancer activity of sorafenib by blocking MCL-1 degradation in hepatocellular carcinoma cells

Objective:Sorafenib is a first-line drug for advanced hepatocellular carcinoma(HCC).Unfortunately,most patients with HCC do not respond to sorafenib,mainly because of the frequent development of drug resistance.Bilirubin is an end metabolite of heme catabolism and an indicator of liver function,but its direct role in regulating the anticancer activity of sorafenib in HCC cells is unclear.In the current study,we aimed to investigate the mechanism of action of bilirubin in sorafenib-mediated tumor suppression in HCC.Methods:A retrospective observational cohort of 100 patients receiving sorafenib was conducted to evaluate the potential role of bilirubin in predicting the prognosis of patients with HCC.Human HCC cell lines were treated with sorafenib in the absence or presence of bilirubin,and cell proliferation,apoptosis,and signaling pathways were assayed.The antagonistic effect of bilirubin toward sorafenib was assessed in nude mice bearing HCC xenografts.Results:Serum levels of bilirubin(including total,direct,and indirect bilirubin)negatively correlated with the overall survival of patients with HCC treated with sorafenib(P<0.05).Both in vitro and in vivo analyses demonstrated that bilirubin significantly abrogated sorafenib-mediated proliferation inhibition and apoptosis induction in HCC cells(P<0.05).Mechanically,bilirubin inhibited sorafenib-induced activation of GSK-3βand subsequent downstream MCL-1 degradation.Conclusions:Our study provides experimental evidence of the antagonistic effect of bilirubin toward sorafenib-mediated anticancer activity in HCC,and it suggests that bilirubin could be used to predict the efficacy of sorafenib treatment.

VPS33B suppresses lung adenocarcinoma metastasis and chemoresistance to cisplatin

The presence of VPS33B in tumors has rarely been reported.Downregulated VPS33B protein expression is an unfavorable factor that promotes the pathogenesis of lung adenocar-cinoma(LUAD).Overexpressed VPS33B was shown to reduce the migration,invasion,metas-tasis,and chemoresistance of LUAD cells to cisplatin(DDP)in vivo and in vitro.Mechanistic analyses have indicated that VPS33B first suppresses epidermal growth factor receptor(EGFR)Ras/ERK signaling,which further reduces the expression of the oncogenic factor C-Myc.Down-regulated c-Myc expression reduces the rate at which it binds the p53 promoter and weakens its transcription inhibition;therefore,decreased C-Myc stimulates p53 expression,leading to decreased epithelial-to-mesenchymal transition(EMT)signal.NESG1 has been shown to be an unfavorable indicator of non-small-cell lung cancer(NSCLC).Here,NESG1 Was identified as an interactive protein of VPS33B.In addition,NESG1 was found to exhibit mutual stimulation with VPS33B via reduced RAS/ERK/c-Jun-mediated transcription repression.Knockdown of NESG1 activated EGFR/Ras/ERK/c-Myc signaling and further downregulated p53 expression,which thus activated EMT signaling and promoted LUAD migration and invasion.Finally,we observed that nicotine suppressed VPS33B expression by inducing PI3K/AKT/c-Jun-mediated transcription suppression.Our study demonstrates that VPS33B as a tumor suppressor is signif-icantly involved in the pathogenesis of LUAD.

Stabilization of MYC G-quadruplex DNA by ruthenium(II)complex overcomes imatinib resistance in chronic myeloid leukemia cells harboring T315I mutation

The key pathogenesis of chronic myeloid leukemia(CML)is the formation of BCR-ABL fusion gene,encoding a 210 kDa Bcr-Abl tyrosine kinase,which is crucial for the occurrence and development of CML.Imatinib(IM)is the first targeted anticancer drug approved by FDA for the treatment of CML;however,some patients,especially those in accelerated phase and blastic phase,develop primary or secondary drug resistance to IM.Particularly,the most challenging resistance is caused by T315I mutation of Bcr-Abl,which represents approximately 15%–20%of all acquired mutations and renders cell resistant to a variety of tyrosine kinase inhibitors.1,2 Thus,there is an urgent need to develop novel strategies to overcome Bcr-Abl T315I-meidated IM resistance.

The dual role of ferroptosis in pancreatic cancer: a narrative review

Pancreatic ductal adenocarcinoma is the main cause of cancer-related mortality,with a lack of effective treatments and overall survival rates far lower than other solid cancers.This clinical challenge is related to late diagnosis as well as primary or acquired resistance to therapy-induced apoptosis.Targeting nonapoptotic cell death pathways may provide alternative therapeutic strategies to overcome drug resistance.In particular,recent studies have suggested that ferroptosis,a type of iron-dependent nonapoptotic cell death,is a promising target for pancreatic ductal adenocarcinoma.Ferroptosis can be triggered by inhibiting or activating the redox or iron metabolism-related pathways,mediated by extrinsic/membrane transports(e.g.,solute carrier family 7 member 11)or intrinsic/enzymes(e.g.,glutathione peroxidase 4).Although the exact effector molecule remains obscure,reactive oxygen species-induced lipid peroxidation and subsequent plasma membrane damage appears to play a central role in mediating ferroptotic death.While treatment-induced ferroptosis is beneficial to suppress tumor growth,inflammation-related immunosuppression caused by ferroptotic damage may promote the occurrence of pancreatic ductal adenocarcinoma.In this review,we outline the latest knowledge about the regulation and function of ferroptosis in pancreatic tumorigenesis and therapy.

Bilirubin inhibits lung carcinogenesis by up-regulating cystatin A expression in tumor-infiltrating macrophages

As one of the leading causes of cancer deaths worldwide,the pathogenesis of lung cancer is still not completely understood.Bilirubin,a product of heme metabolism,has long been considered a waste product of the body.Increasing evidence suggests that bilirubin has additional antioxidant,anti-inflammatory,and proteasome inhibitory activities.However,the specific role of bilirubin in the formation and development of lung cancer has not been elucidated.

Cancer stem cell-mediated therapeutic resistance in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a highly heterogeneous malignancy.In the clinic,therapeutic resistance is largely attributed to tumor heterogeneity.Growing evidence indicates that cancer stem cells(CSCs)are the major source of tumor heterogeneity.Hence,uncovering the resistance mechanisms associated with CSC properties is essential for developing effective therapeutics.CSCs resemble embryonic stem cells.Embryonic developmentrelated genes and signaling pathways are usually abnormally active and function as oncofetal drivers in HCC.Multiple strategies have been applied to identify oncofetal drivers.The mechanisms of CSC resistance could also provide reliable biomarkers to predict treatment failure.Precisely targeting these specific CSC properties may be effective in preventing or annihilating therapy resistance.This review provides an overview of drug resistance mechanisms associated with CSC traits and summarize therapeutic strategies against drug resistance.