RESUMO
BACKGROUND: Cholangiocarcinoma (CCA) has a poor prognosis and only limited palliative treatment options. The deficiency of adiponectin and adenosine monophosphate-activated protein kinase (AMPK) signaling was reported in several malignancies, but the alteration of these proteins in CCA is still unclear. OBJECTIVES: This study aimed to assess the role of adiponectin and AMPK signaling in CCA. Furthermore, AdipoRon, a novel adiponectin receptor (AdipoR) agonist, was evaluated in vitro and in vivo as a new anti-tumor therapy for CCA. METHODS: The expression of AdipoR1 and p-AMPKα in human tissue microarrays (TMAs) was evaluated by immunohistochemistry staining (IHC). The effect of 2-(4-Benzoylphenoxy)-N-[1-(phenylmethyl)-4-piperidinyl]-acetamide (AdipoRon) was investigated in vitro with proliferation, crystal violet, migration, invasion, colony formation, senescence, cell cycle and apoptosis assays and in vivo using a CCA engineered mouse model (AlbCre/LSL-KRASG12D/p53L/L). RT-qPCR and western blot methods were applied to study molecular alterations in murine tissues. RESULTS: AdipoR1 and p-AMPKα were impaired in human CCA tissues, compared to adjacent non-tumor tissue. There was a positive correlation between the AdipoR1 and p-AMPKα levels in CCA tissues. Treatment with AdipoRon inhibited proliferation, migration, invasion and colony formation and induced apoptosis in a time- and dose-dependent manner in vitro (p<0.05). In addition, AdipoRon reduced the number of CCA and tumor volume, prolonged survival, and decreased metastasis and ascites in the treated group compared to the control group (p<0.05). CONCLUSIONS: AdipoR1 and p-AMPKα are impaired in CCA tissues, and AdipoRon effectively inhibits CCA in vitro and in vivo. Thus, AdipoRon may be considered as a potential anti-tumor therapy in CCA.
Assuntos
Proteínas Quinases Ativadas por AMP , Apoptose , Neoplasias dos Ductos Biliares , Proliferação de Células , Colangiocarcinoma , Receptores de Adiponectina , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Colangiocarcinoma/metabolismo , Receptores de Adiponectina/metabolismo , Receptores de Adiponectina/agonistas , Humanos , Animais , Proteínas Quinases Ativadas por AMP/metabolismo , Camundongos , Proliferação de Células/efeitos dos fármacos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/metabolismo , Apoptose/efeitos dos fármacos , Piperidinas/farmacologia , Piperidinas/química , Piperidinas/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Movimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Hepatocellular carcinoma (HCC) is the second lethal cancer. Short overall survival, low five-year survival rate, and unimproved treatment efficacy urge the need to improve HCC prognosis. Adiponectin is key protector against cancer and hepatic abnormalities. Hypoadiponectinemia occurs in and promotes carcinogenesis and hepatic diseases. Adiponectin reactivation by different methods showed impressive effect against cancer and hepatic diseases. Recently, AdipoRon, an adiponectin receptor agonist, can interact with both Adiponectin receptors. AdipoRon showed promising anti-cancer effect in some cancers, but no study on HCC yet. The in vitro effect of AdipoRon on HCC was investigated by cell viability, migration, invasion, colony formation and apoptosis assays. The signalling alteration was determined by RT-qPCR and Western blot. The effect of treatment was interpreted by comparison between treatments and control. The difference between two cell lines was relatively compared. Our results showed significant in vitro anti-cancer effect of AdipoRon via AMPK- and dose-dependent manner. Huh7 cells showed a lower level of AdipoR1/2 and a superior proliferation and aggressiveness, compared to Hep3B. In addition, Huh7 cells were more sensitive to AdipoRon treatment (lower IC50, less cell growth, migration, invasion and colonies upon AdipoRon treatment) than Hep3B cells. In conclusion, AdipoRon effectively inhibited HCC growth and invasiveness in vitro. The deficient expression of adiponectin receptors affects efficacy of AdipoRon and aggressiveness of HCC cells.
RESUMO
Chimeric antigen receptor (CAR) T cells and PD-1 antibodies (PD-1 Ab) are emergent immunotherapies with unprecedented efficacy. The presence of PD-1 on T cells contributes to hypofunction of CAR-T therapy and inhibition of PD-1 enhances anti-cancer effect of CAR-T cells. Therefore, the combination of CAR-T cells and PD-1 antibody is a promissing strategy for cancer treatment. This study aims to establish our in-house CAR-T cells and evaluate the safety of CAR-T cells in combination with PD-1 antibody in animals. The toxicity of CD19-CAR-T cells was examined using Swiss Webster mice. Four mouse groups were treated with control, CAR-T, PD-1 antibody or CAR-T + PD-1 antibody. Mice's overall status was monitored and recorded. At the end-point, hematological and biochemical indices were quantified, histopathology of liver and kidney was evaluated by pathologists. The relative abnormal ratio and absolute values were compared between groups. We generated our in-house CAR-T cells and used them for safety evaluation in mice. The increase in mouse weight was observed in all groups after treatment and the weight was comparable between groups. The hematological, biochemical and histopathological parameters were equivalent between groups, except for liver grain degeneration occurred in treatment groups. Thus, CAR-T cells, PD-1 Ab and their combination were safe in mice. We successfully produced our in-house CAR-T cells and the combination of our CAR-T cells and PD-1 antibody was safe in mice with comparable values of hematopoietic indices, liver and kidney functions. Longer follow-up might be necessary to evaluate their effect on the liver.
Assuntos
Receptores de Antígenos de Linfócitos T , Receptores de Antígenos Quiméricos , Camundongos , Animais , Receptor de Morte Celular Programada 1 , Linhagem Celular Tumoral , Linfócitos T , Anticorpos , Imunoterapia Adotiva , Modelos TeóricosRESUMO
BACKGROUND: Ovarian cancer is one of the most aggressive types of gynecologic cancers. Many patients have a relapse within two years after diagnosis and subsequent therapy. Among different genetic changes generally believed to be important for the development of cancer, TP53 is the most common mutation in the case of ovarian tumors. OBJECTIVE: Our work aims to analyze the outcomes of different comparisons based on the overall survival of ovarian cancer patients, the determination of TP53 status and the amount of p53 protein in tumor tissues. METHODS: We analyzed and compared a collective of 436 ovarian patients' data. The extracted data include TP53 mutation status, p53 protein level and information on the overall survival. Values for p53 protein level in dependence of the TP53 mutation status were compared using the Independent Samples t-Test. Survival analyses were displayed by Kaplan- Meier plots, using the log-rank test to check for statistical significance. RESULTS: We have not found any statistically significant correlations between the determination of TP53 status or the amount of p53 protein in tumor tissues and the overall survival of ovarian cancer patients. CONCLUSION: In ovarian tumors the determination of both the TP53 status as well as the p53 protein amount has only limited diagnostic importance.
Assuntos
Neoplasias Ovarianas , Proteína Supressora de Tumor p53 , Feminino , Humanos , Mutação , Recidiva Local de Neoplasia/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Prognóstico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: Cholangiocarcinoma (CCA) is the second most common hepatobiliary cancer and associated with a poor prognosis. Only one-third of CCA cases are diagnosed at operable stages. However, a high rate of relapse has been observed postoperatively. Besides screening for operable individuals, efficacious therapeutic for recurrent and advanced CCA is urgently needed. The treatment outcome of available therapeutics is important to clarify clinical indication and facilitate the development of treatment strategies. OBJECTIVE: This review aims to compare the treatment outcome of different therapeutics based on both overall survival and progression-free survival. METHODS: Over one hundred peer-reviewed articles were examined. We compared the treatment outcome between different treatment methods, including tumor resection with or without postoperative systematic therapy, chemotherapies including FOFLOX, and targeted therapies, such as IDH1, K-RAS, and FGFR inhibitors. Notably, the scientific basis and outcome of available treatment methods were compared with the standard first-line therapy. RESULTS: CCAs at early stages should firstly undergo tumor resection surgery, followed by postoperative treatment with Capecitabine. Chemotherapy can be considered as a preoperative option for unresectable CCAs. Inoperable CCAs with genetic aberrances like FGFR alterations, IDH1, and KRAS mutations should be considered with targeted therapies. Fluoropyrimidine prodrug (S-1)/Gemcitabine/Cisplatin and nab-Paclitaxel/Gemcitabine/Cisplatin show favorable outcome which hints at the triplet regimen to be superior to Gemcitabine/Cisplatin on CCA. The triplet chemotherapeutic should be tested further compared to Gemcitabine/Cisplatin among CCAs without genetic alterations. Gemcitabine plus S-1 was recently suggested as the convenient and equivalent standard first-line for advanced/recurrent biliary tract cancer. CONCLUSION: This review provides a comparative outcome between novel targeted therapies and currently available therapeutics.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma/tratamento farmacológico , Cisplatino/uso terapêutico , Humanos , Recidiva Local de Neoplasia/tratamento farmacológicoRESUMO
BACKGROUND AND AIM: Cholangiocarcinoma has an unimproved prognosis. Interleukin 6 (IL-6) has an oncogenic potential in some cancer diseases. However, the role of IL-6 in cholangiocarcinoma carcinogenesis is not well understood. The current study investigated the role of IL-6 signaling in cholangiocarcinoma carcinogenesis and efficacy of siltuximab treatment on cholangiocarcinoma in vitro and in vivo. METHODS: The expression of IL-6 was analyzed on human cholangiocarcinoma cell lines and murine and human cholangiocarcinoma tissues, using reverse transcription real-time polymerase chain reaction and immunohistochemistry. In addition, the effect of anti-IL-6 chimeric monoclonal antibody, siltuximab, was investigated in vitro by proliferation, migration, and two-dimensional and three-dimensional invasion assays and in vivo by xenograft mouse model. Western blot was applied to study the molecular alteration. RESULTS: Our result shows high expression of IL-6 in human cholangiocarcinoma cells, and IL-6 stimulants enhance cholangiocarcinoma cell proliferation. In addition, murine and human cholangiocarcinoma tissues express significantly higher levels of IL-6, compared with adjacent non-tumor tissues. On the cholangiocarcinoma engineered mouse model, IL-6 level is associated with tumor volume. Taken together, our data indicate an oncogenic potential of IL-6 in cholangiocarcinoma carcinogenesis. Siltuximab sufficiently abrogates IL-6 signaling and inhibits cholangiocarcinoma progression in vitro and in vivo. The results additionally indicate a relative alteration of IL-6 signaling and its molecular targets, such as STAT3, Wnt/ß-catenin, and mesenchymal markers. CONCLUSIONS: Interleukin 6 plays an essential role in cholangiocarcinoma carcinogenesis, and siltuximab has the potential to be considered as a new treatment option for cholangiocarcinoma patients.
Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Carcinogênese/genética , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Interleucina-6/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Neoplasias dos Ductos Biliares/genética , Linhagem Celular Tumoral , Colangiocarcinoma/genética , Modelos Animais de Doenças , Expressão Gênica , Humanos , Interleucina-6/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Fator de Transcrição STAT3 , Proteínas Wnt , beta CateninaRESUMO
Cell-to-cell transmission of the unfolded protein response (UPR) is one of the most exciting observations recently made in cell biology. One of the most efficient tools to induce UPR response in cell culture is treatment with specific compounds leading to accumulation of misfolded proteins in endoplasmic reticulum. In this article we discussed opposite opinions regarding application of this approach and possible sources of experimental artefacts.
Assuntos
Estresse do Retículo Endoplasmático , Resposta a Proteínas não Dobradas , Retículo Endoplasmático/metabolismoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) represents a major health burden with limited curative treatment options. There is a substantial unmet need to develop innovative approaches to impact the progression of advanced HCC. Haprolid is a novel natural component isolated from myxobacteria. Haprolid has been reported as a potent selective cytotoxin against a panel of tumor cells in recent studies including HCC cells. The aims of this study are to evaluate the antitumor effect of haprolid in HCC and to understand its underlying molecular mechanisms. METHODS: The efficacy of haprolid was evaluated in human HCC cell lines (Huh-7, Hep3B and HepG2) and xenograft tumors (NMRI-Foxn1nu mice with injection of Hep3B cells). Cytotoxic activity of haprolid was determined by the WST-1 and crystal violet assay. Wound healing, transwell and tumorsphere assays were performed to investigate migration and invasion of HCC cells. Apoptosis and cell-cycle distribution were measured by flow cytometry. The effects of haprolid on the Rb/E2F and Akt/mTOR pathway were examined by immunoblotting and immunohistochemistry. RESULTS: haprolid treatment significantly inhibited cell proliferation, migration and invasion in vitro. The epithelial-mesenchymal transition (EMT) was impaired by haprolid treatment and the expression level of N-cadherin, vimentin and Snail was downregulated. Moreover, growth of HCC cells in vitro was suppressed by inhibition of G1/S transition, and partially by induction of apoptosis. The drug induced downregulation of cell cycle regulatory proteins cyclin A, cyclin B and CDK2 and induced upregulation of p21 and p27. Further evidence showed that these effects of haprolid were associated with Rb/E2F downregulation and Akt/mTOR inhibition. Finally, in vivo nude mice experiments demonstrated significant inhibition of tumor growth upon haprolid treatment. CONCLUSION: Our results show that haprolid inhibits the growth of HCC through dual inhibition of Rb/E2F and Akt/mTOR pathways. Therefore, haprolid might be considered as a new and promising candidate for the palliative therapy of HCC.
RESUMO
Aberrant activation of Sonic Hedgehog (SHH) pathway has been implicated in a variety of cancers including cholangiocarcinoma (CC); however, the influencing factors are still unknown. Additionally, intratumoral hypoxia is known to contribute towards therapeutic resistance through modulatory effects on various pathways. In this study, we investigated the relationship between hypoxia and SHH pathway activation and the effect of this interplay on cancer stemness and epithelial-to- mesenchymal transition (EMT) during cholangiocarcinogenesis. Hypoxia promoted SHH pathway activation, evidenced by upregulated SHH and SMO levels, and enhanced glioma-associated oncogene homolog 1 (GLI1) nuclear translocation; whereas silencing of HIF-1α impaired SHH upregulation. Hypoxia also enhanced the expression of cancer stem cell (CSC) transcription factors (NANOG, Oct4, SOX2), CD133 and EMT markers (N-cadherin, Vimentin), thereby supporting invasion. Cyclopamine treatment suppressed hypoxia induced SHH pathway activation, consequently reducing invasiveness by downregulating the expression of CSC transcription factors, CD133 and EMT. Cyclopamine induced apoptosis in CC cells under hypoxia, suggesting that hypoxia induced activation of SHH pathway has modulatory effects on CC progression. Therefore, SHH signaling is proposed as a target for CC treatment, which is refractory to standard chemotherapy.
Assuntos
Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Transição Epitelial-Mesenquimal , Proteínas Hedgehog/metabolismo , Oxigênio/metabolismo , Transdução de Sinais , Antígeno AC133/genética , Antígeno AC133/metabolismo , Apoptose , Hipóxia Celular , Linhagem Celular Tumoral , Movimento Celular , Proteínas Hedgehog/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/fisiologia , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Receptor Smoothened/genética , Receptor Smoothened/metabolismo , Alcaloides de Veratrum/farmacologia , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismoRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0077433.].
RESUMO
Cholangiocarcinoma (CC) is the second most common primary hepatic malignancy. CC treatment options are very limited especially for patients with distant metastasis. Kangai 1 C-terminal interacting tetraspanin (KITENIN) is highly expressed in numerous cancers, but the role of KITENIN in CC remains unknown. Here, we have investigated for the first time the function of KITENIN in human CC cell lines (TFK-1, SZ-1), tissues and a CC mouse model (Alb-Cre/LSL-KRASG12D/p53L/L). KITENIN was expressed in 92.2% of human CC tissues, in murine CC samples and also in human CC cell lines. Knockdown of KITENIN by small interfering RNA (siRNA) effectively reduced proliferation, migration, invasion and colony formation in both intra- and extra-hepatic CC cells. The expression of epithelial-mesenchymal transition (EMT) markers like N-cadherin, Vimentin, Snail and Slug were suppressed in KITENIN knockdown CC cells. Our results indicate that KITENIN is crucial for cholangiocarcinogenesis and it might become a potential therapeutic target for human CC treatment.
Assuntos
Neoplasias dos Ductos Biliares/prevenção & controle , Proteínas de Transporte/antagonistas & inibidores , Proliferação de Células , Colangiocarcinoma/prevenção & controle , Inativação Gênica , Proteínas de Membrana/antagonistas & inibidores , RNA Interferente Pequeno/genética , Animais , Apoptose , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Movimento Celular , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Feminino , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Células Tumorais CultivadasRESUMO
Amongst all currently used drugs in the field of cancer therapy, the most prominent group of agents which induce DNA, damage both directly or indirectly. Intuitively DNA should not be a perfect target for relatively unspecific small molecular weight drugs. However, the current understanding is that not damage per se but cellular response to DNA damage induced by antitumor agents is responsible for their specific targeted effect towards cancer cells in comparison to the normal cells. DNA damaging chemotherapeutics include compounds with diferent activities namely: directly or indirectly induce DNA strand breaks, covalently modify DNA bases, change the chromatin structure and topology by inhibiting chromatin-modifying enzymes. In this special issue of Current Medicinal Chemistry entitled....
Assuntos
Antineoplásicos/toxicidade , Dano ao DNA/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Cromatina/química , Cromatina/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologiaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited treatment options. The proteasome inhibitor Argyrin A, a cyclic peptide derived from the myxobacterium Archangium gephyra, shows antitumoral activities. We hypothesize that his analogue Argyrin F (AF) may also prevent PDAC progression. We have used PDAC cells and engineered mice (Pdx1-Cre; LSL-KrasG12D; p53 lox/+) to assess AF anticancer activity. We analyzed the effect of AF on proliferation and epithelial plasticity using MTT-, wound healing-, invasion-, colony formation-, apoptosis-, cell cycle- and senescence assays. In vivo treatment with AF, Gemcitabine (G) and combinational treatment (AF + G) was performed for survival analysis. AF inhibited cell proliferation, migration, invasion and colony formation in vitro. AF impaired epithelial-mesenchymal transition (EMT), caused considerable apoptosis and senescence in a dose- and time-dependent manner and affected cell cycle G1/S phase transition. G treatment achieved longest mice survival, followed by AF + G and AF compared to vehicle group. However, AF + G treatment induced the largest reduction in tumor spread and ascites. In conclusion, we have demonstrated that AF prevents PDAC progression and that combined therapy was superior to AF monotherapy. Therefore, AF treatment might be useful as an additional therapy for PDAC.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Peptídeos Cíclicos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma Ductal Pancreático/irrigação sanguínea , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/secundário , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Camundongos Transgênicos , Invasividade Neoplásica , Neovascularização Patológica , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Estabilidade Proteica , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Carga Tumoral/efeitos dos fármacosRESUMO
Cancer stem cells (CSC) are associated with tumor resistance and are characterized in gastric cancer (GC). Studies have indicated that Notch and wnt-beta-catenin pathways are crucial for CSC development. Using CD44+ CSCs, we investigated the role of these pathways in GC carcinogenesis. We performed cell proliferation, wound healing, invasion, tumorsphere, and apoptosis assays. Immunoblot analysis of downstream signaling targets of Notch and wnt-beta-catenin were tested after gamma-secretase inhibitor IX (GSI) treatment. Immunohistochemistry, immunofluorescence, and Fluorescence activated cell sorting (FACS) were used to determine CD44 and Hairy enhancer of split-1 (Hes1) expression in human GC tissues. CD44+ CSCs were subcutaneously injected into NMR-nu/nu mice and treated with vehicle or GSI. GC patients with expression of CD44 and Hes1 showed overall reduced survival. CD44+ CSCs showed high expression of Hes1. GSI treatment showed effective inhibition of cell proliferation, migration, invasion, tumor sphere formation of CD44+ CSCs, and induced apoptosis. Importanly, Notch1 was found to be important in mediating a crosstalk between Notch and wnt-beta-catenin in CD44+ CSCs. Our study highlights a crosstalk between Notch and wnt-beta-catenin in gastric CD44+ CSCs. Expression of CD44 and Hes1 is associated with patient overall survival. GSI could be an alternative drug to treat GC. Stem Cells Translational Medicine 2017;6:819-829.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Receptores de Hialuronatos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Receptores Notch/metabolismo , Neoplasias Gástricas/patologia , Via de Sinalização Wnt , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Camundongos Nus , Invasividade Neoplásica , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Análise de Sobrevida , Fatores de Transcrição HES-1/metabolismo , Regulação para Cima/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0095605.].
RESUMO
MYC oncoproteins are involved in the genesis and maintenance of the majority of human tumors but are considered undruggable. By using a direct in vivo shRNA screen, we show that liver cancer cells that have mutations in the gene encoding the tumor suppressor protein p53 (Trp53 in mice and TP53 in humans) and that are driven by the oncoprotein NRAS become addicted to MYC stabilization via a mechanism mediated by aurora kinase A (AURKA). This MYC stabilization enables the tumor cells to overcome a latent G2/M cell cycle arrest that is mediated by AURKA and the tumor suppressor protein p19(ARF). MYC directly binds to AURKA, and inhibition of this protein-protein interaction by conformation-changing AURKA inhibitors results in subsequent MYC degradation and cell death. These conformation-changing AURKA inhibitors, with one of them currently being tested in early clinical trials, suppressed tumor growth and prolonged survival in mice bearing Trp53-deficient, NRAS-driven MYC-expressing hepatocellular carcinomas (HCCs). TP53-mutated human HCCs revealed increased AURKA expression and a positive correlation between AURKA and MYC expression. In xenograft models, mice bearing TP53-mutated or TP53-deleted human HCCs were hypersensitive to treatment with conformation-changing AURKA inhibitors, thus suggesting a therapeutic strategy for this subgroup of human HCCs.
Assuntos
Aurora Quinase A/metabolismo , Carcinoma Hepatocelular/genética , Hepatócitos/metabolismo , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Aurora Quinase A/antagonistas & inibidores , Azepinas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Pontos de Checagem do Ciclo Celular , Inibidor p16 de Quinase Dependente de Ciclina/genética , Deleção de Genes , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Camundongos , Camundongos Knockout , Terapia de Alvo Molecular , Mutação , Proteína Oncogênica p21(ras)/metabolismo , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , RNA Interferente Pequeno , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Chronic lymphocytic leukemia (CLL), a clonal expansion of B CD5+ cells, is the most common type of adult leukemia in western countries. The accumulation of neoplastic B-cells is primarily caused by prolonged life-span of these cells due to deregulation of apoptosis, and only marginally due to a higher proliferation rate. In spite of numerous reports characterizing particular mechanisms of B-CLL cell apoptosis, still relatively little is known about the complex regulation of this process. Therefore, more detailed research is required to understand the complicated mechanisms and regulatory processes of apoptosis in neoplastic B lymphocytes.