RESUMO
Hepatocellular carcinoma (HCC) poses a significant threat to human health. Resistance to sorafenib in the chemotherapy of HCC is a common and significant issue that profoundly impacts clinical treatment. While several members of the transmembrane (TMEM) protein family have been implicated in the occurrence and progression of HCC, the association between TMEM39b and HCC remains unexplored. This study revealed a significant overexpression of TMEM39b in HCC, which correlated with a poor prognosis. Subsequent investigation revealed that RAS-selective lethal 3 (RSL3) induced pronounced ferroptosis in HCC, and knocking down the expression of TMEM39b significantly decreased its severity. Similarly, following the induction of ferroptosis in HCC by sorafenib, knocking down the expression of TMEM39b also decreased the severity of ferroptosis, enhancing HCC tolerance to sorafenib. In conclusion, we propose that TMEM39b promotes tumor progression and resistance to sorafenib by inhibiting ferroptosis in HCC.
Assuntos
Carcinoma Hepatocelular , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Ferroptose , Neoplasias Hepáticas , Proteínas de Membrana , Sorafenibe , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Humanos , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Ferroptose/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Linhagem Celular Tumoral , Camundongos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Prognóstico , Regulação Neoplásica da Expressão Gênica , Masculino , Ensaios Antitumorais Modelo de Xenoenxerto , FemininoRESUMO
BACKGROUND: Primary cancer of the appendix is rare and often difficult to diagnose preoperatively due to the lack of specific clinical symptoms. Autoimmune encephalitis (AIE) is the most common cause of non-infectious encephalitis. The etiologies of AIE include tumors (paraneoplastic), infections (parainfections), or recessive infections. The tumors that have been reported to cause AIE include thymomas, ovarian teratomas, lung cancers, and breast cancers. However, there are no reports of AIE occurring after surgery for appendiceal cancer. This report describes the diagnosis and treatment of a patient with an appendiceal cancer and postoperative AIE. CASE SUMMARY: We report the case of a 47-year-old man who was transferred to our hospital due to a recurrent low intestinal obstruction. Abdominal enhanced computed tomography was used to consider the possibility of a terminal ileal tumor with serous infiltration and lymph node metastasis. A right hemi-colectomy was performed under general anesthesia with an ileo-transcolon anastomosis and laparoscopic exploration. The postoperative pathologic evaluation revealed a high-grade goblet cell carcinoma of the appendix, accompanied by mesangial and abdominal lymph node metastases, and neural tube and vascular infiltration. The operation was completed without complication. The patient developed restlessness on postoperative day 4, and gradually developed a disturbance of consciousness on postoperative day 6. He was transferred to West China Hospital of Sichuan University and diagnosed with AIE. CONCLUSION: Albeit rare, the occurrence of neurologic and psychiatric symptoms in patients with an appendiceal cancer postoperatively suggests the possibility of AIE.
RESUMO
BACKGROUND AND AIMS: The single dose of 2 L polyethylene glycol (PEG) has shown high cleaning efficacy and tolerability in low-risk patients. However, the dosage of this regimen is still challenging for many patients. We investigated the efficacy and tolerability of a novel ultra-low-volume regimen using 1 L PEG and linaclotide (1 L PEG+L) versus a single dose of 2 L PEG in low-risk patients. METHODS: In this prospective, randomized, observer-blinded, multicenter study, low-risk adult patients scheduled for colonoscopy were enrolled and randomized (1:1) to receive the 1 L PEG+L regimen or the 2 L PEG regimen. The primary outcome was the effectiveness of bowel cleansing according to the Boston Bowel Preparation Scale. Secondary outcomes included cecal intubation rate, cecal insertion time, withdrawal time, polyp detection rate and adenoma detection rate, tolerability, adverse events, and willingness to repeat bowel preparation. The full analysis set (FAS) and per-protocol set (PPS) were used for statistical analyses. RESULTS: A total of 548 patients comprised the FAS, and 522 patients comprised the PPS. Noninferiority on adequate bowel cleansing of 1 L PEG+L vs 2 L PEG was established both in FAS (90.5% vs 91.6%, P = .644) and PPS (90.3% vs 92.4%, P = .390). There were no significant differences regarding the total score and each segment scores of the Boston Bowel Preparation Scale, cecal intubation rate, cecal insertion time, withdrawal time, polyp detection rate, and adenoma detection rate (all, P > .05). However, patients in the 1 L PEG+L group reported less nausea (7.7% vs 17.1%, P < .01) and vomiting (4.0% vs 10.9%, P < .01) and had a higher willingness to repeat bowel preparation (95.2% vs 82.2%, P < .01). CONCLUSIONS: The regimen of 1 L PEG+L was not inferior to 2 L PEG on colon cleansing, with better tolerability and higher willingness to repeat the bowel preparation in a low-risk population. (Clinical trial registration number: ChiCTR2100053273.).
Assuntos
Adenoma , Polietilenoglicóis , Adulto , Humanos , Colonoscopia/métodos , Catárticos , Ceco , Estudos ProspectivosRESUMO
Due to the body's systemic distribution of photothermal agents (PTAs), and to the imprecise exposure of lasers, photothermal therapy (PTT) is challenging to use in treating tumor sites selectively. Striving for PTT with high selectivity and precise treatment is nevertheless important, in order to raise the survival rate of cancer patients and lower the likelihood of adverse effects on other body sections. Here, we studied cold atmospheric plasma (CAP) as a supplementary procedure to enhance selectivity of PTT for cancer, using the classical photothermic agent's gold nanostars (AuNSs). In in vitro experiments, CAP decreases the effective power of PTT: the combination of PTT with CAP at lower power has similar cytotoxicity to that using higher power irradiation alone. In in vivo experiments, combination therapy can achieve rapid tumor suppression in the early stages of treatment and reduce side effects to surrounding normal tissues, compared to applying PTT alone. This research provides a strategy for the use of selective PTT for cancer, and promotes the clinical transformation of CAP.
Assuntos
Neoplasias , Fotoquimioterapia , Gases em Plasma , Linhagem Celular Tumoral , Ouro/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Fototerapia , Terapia Fototérmica , Gases em Plasma/farmacologia , Gases em Plasma/uso terapêuticoRESUMO
Studies have shown that disulfiram (DSF) can combine with Cu2+ to form bis(N, N-diethyldithiocarbamate) copper(II) complex (CuET) as antitumor drugs. However, there is insufficient endogenous Cu2+ dose to eradicate cancer cells selectively. Inspired by the buffet, we use Cu2+ doped hollow zeolitic imidazolate framework nanoparticles (HZIFCu) as the carrier and equipped with DSF and indocyanine green (ICG) and targeted by folic acid (FA) (D&I@HZIFCu-FA) to enhance DSF-based cancer therapy. D&I@HZIFCu-FA could effectively supply Cu2+ by a buffet-style, assisting the "DSF-to-CuET" transformation in the tumor. Additionally, self-supply Cu2+ could convert H2O2 into ·OH by triggering a Fenton-like reaction for chemo-dynamic therapy, and ICG achieves photothermal therapy for tumors under laser irradiation. This work provides a buffet-style for Cu2+ to make DSF a strong candidate for cancer treatment by combining chemotherapy, chemo-dynamic therapy, and photothermal therapy and inspires more research about its applications in tumor therapy.
Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cobre , Dissulfiram/farmacologia , Peróxido de Hidrogênio , Neoplasias/tratamento farmacológicoRESUMO
B-cell activating factor (BAFF) is a crucial survival factor for B cells, and excess BAFF contributes to development of autoimmune diseases. Recent studies have shown that rapamycin can prevent BAFF-induced B-cell proliferation and survival, but the underlying mechanism remains to be elucidated. Here we found that rapamycin inhibited human soluble BAFF (hsBAFF)-stimulated cell proliferation by inducing G1-cell cycle arrest, which was through downregulating the protein levels of CDK2, CDK4, CDK6, cyclin A, cyclin D1, and cyclin E. Rapamycin reduced hsBAFF-stimulated cell survival by downregulating the levels of anti-apoptotic proteins (Mcl-1, Bcl-2, Bcl-xL and survivin) and meanwhile upregulating the levels of pro-apoptotic proteins (BAK and BAX). The cytostatic and cytotoxic effects of rapamycin linked to its attenuation of hsBAFF-elevated intracellular free Ca2+ ([Ca2+]i). In addition, rapamycin blocked hsBAFF-stimulated B-cell proliferation and survival by preventing hsBAFF from inactivating PTEN and activating the Akt-Erk1/2 pathway. Overexpression of wild type PTEN or ectopic expression of dominant negative Akt potentiated rapamycin's suppression of hsBAFF-induced Erk1/2 activation and proliferation/viability in Raji cells. Interestingly, PP242 (mTORC1/2 inhibitor) or Akt inhibitor X, like rapamycin (mTORC1 inhibitor), reduced the basal or hsBAFF-induced [Ca2+]i elevations. Chelating [Ca2+]i with BAPTA/AM, preventing [Ca2+]i elevation using EGTA, 2-APB or verapamil, inhibiting CaMKII with KN93, or silencing CaMKII strengthened rapamycin's inhibitory effects. The results indicate that rapamycin inhibits BAFF-stimulated B-cell proliferation and survival by blunting mTORC1/2-mediated [Ca2+]i elevations and suppressing Ca2+-CaMKII-dependent PTEN/Akt-Erk1/2 signaling pathway. Our finding underscores that rapamycin may be exploited for prevention of excessive BAFF-induced aggressive B-cell malignancies and autoimmune diseases.
Assuntos
Fator Ativador de Células B/metabolismo , Linfócitos B/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cálcio/metabolismo , Linfoma de Células B/patologia , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirolimo/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quinases Ciclina-Dependentes/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Linfoma de Células B/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Modelos BiológicosRESUMO
B cell activating factor from the TNF family (BAFF) is implicated in not only the physiology of normal B cells, but also the pathophysiology of aggressive B cells related to malignant and autoimmune diseases. Autophagy plays a crucial role in balancing the beneficial and detrimental effects of immunity and inflammation. However, little is known about whether and how excessive BAFF mediates autophagy contributing to B-cell proliferation and survival. Here, we show that excessive human soluble BAFF (hsBAFF) inhibited autophagy with a concomitant reduction of LC3-II in normal and B-lymphoid (Raji) cells. Knockdown of LC3 not only potentiated hsBAFF inhibition of autophagy, but also attenuated hsBAFF activation of Akt/mTOR pathway, thereby diminishing hsBAFF-induced B-cell proliferation/viability. Further, we found that hsBAFF inhibition of autophagy was Akt/mTOR-dependent. This is supported by the findings that hsBAFF increased mTORC1-mediated phosphorylation of ULK1 (Ser757); Akt inhibitor X, mTORC1 inhibitor rapamycin, mTORC1/2 inhibitor PP242, expression of dominant negative Akt, or knockdown of mTOR attenuated hsBAFF-induced phosphorylation of ULK1, decrease of LC3-II level, and increase of cell proliferation/viability. Chelating intracellular free Ca2+ ([Ca2+]i) with BAPTA/AM or preventing [Ca2+]i elevation using EGTA or 2-APB profoundly blocked hsBAFF-induced activation of Akt/mTOR, phosphorylation of ULK1 and decrease of LC3-II, as well as increase of cell proliferation/viability. Similar effects were observed in the cells where CaMKII was inhibited by KN93 or knocked down by CaMKII shRNA. Collectively, these results indicate that hsBAFF inhibits autophagy promoting cell proliferation and survival through activating Ca2+-CaMKII-dependent Akt/mTOR signaling pathway in normal and neoplastic B-lymphoid cells. Our findings suggest that manipulation of intracellular Ca2+ level or CaMKII, Akt, or mTOR activity to promote autophagy may be exploited for prevention of excessive BAFF-induced aggressive B lymphocyte disorders and autoimmune diseases.
Assuntos
Autofagia , Fator Ativador de Células B/metabolismo , Linfócitos B/patologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Linfócitos B/citologia , Linfócitos B/metabolismo , Cálcio/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Humanos , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismoRESUMO
B cell activating factor from the TNF family (BAFF) stimulates B-cell proliferation and survival, but excessive BAFF promotes the development of aggressive B cells leading to malignant and autoimmune diseases. Recently, we have reported that rapamycin, a macrocyclic lactone, attenuates human soluble BAFF (hsBAFF)-stimulated B-cell proliferation/survival by suppressing mTOR-mediated PP2A-Erk1/2 signaling pathway. Here, we show that the inhibitory effect of rapamycin on hsBAFF-promoted B cell proliferation/survival is also related to blocking hsBAFF-stimulated phosphorylation of Akt, S6K1, and 4E-BP1, as well as expression of survivin in normal and B-lymphoid (Raji and Daudi) cells. It appeared that both mTORC1 and mTORC2 were involved in the inhibitory activity of rapamycin, as silencing raptor or rictor enhanced rapamycin's suppression of hsBAFF-induced survivin expression and proliferation/viability in B cells. Also, PP242, an mTORC1/2 kinase inhibitor, repressed survivin expression, and cell proliferation/viability more potently than rapamycin (mTORC1 inhibitor) in B cells in response to hsBAFF. Of interest, ectopic expression of constitutively active Akt (myr-Akt) or constitutively active S6K1 (S6K1-ca), or downregulation of 4E-BP1 conferred resistance to rapamycin's attenuation of hsBAFF-induced survivin expression and B-cell proliferation/viability, whereas overexpression of dominant negative Akt (dn-Akt) or constitutively hypophosphorylated 4E-BP1 (4EBP1-5A), or downregulation of S6K1, or co-treatment with Akt inhibitor potentiated the inhibitory effects of rapamycin. The findings indicate that rapamycin attenuates excessive hsBAFF-induced cell proliferation/survival via blocking mTORC1/2 signaling in normal and neoplastic B-lymphoid cells. Our data underscore that rapamycin may be a potential agent for preventing excessive BAFF-evoked aggressive B-cell malignancies and autoimmune diseases.
Assuntos
Antineoplásicos/farmacologia , Fator Ativador de Células B/metabolismo , Linfócitos B/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linfoma de Células B/tratamento farmacológico , Complexos Multiproteicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linfócitos B/enzimologia , Linfócitos B/patologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma de Células B/genética , Linfoma de Células B/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , TransfecçãoRESUMO
BACKGROUND/AIMS: Paclitaxel (PTX) is one of the most effective anti-cancer drugs. However, multiple drug resistance is still the main factor that hinders the effective treatment of cancer with PTX. Several factors including YAP over-expression can cause PTX resistance. In this study, we aimed to verify the role YAP plays in PTX resistance, explore the reversal of PTX resistance by verteporfin (VP) and investigate the effect of combination therapy of PTX and VP on the PTX resistant colon cancer cells (HCT-8/T). METHODS: To study the relationship between YAP and PTX resistance, a stable YAP-over-expression or YAP silencing cell line was generated by transfected with YAP-plasmids or siYAP-RNA. WST-1 assay was performed to detect the cytotoxicity of PTX on HCT-8 and HCT-8/T cells. Clone formation assay and Transwell assay was preformed to determine the cell proliferation and invasion ability respectively. Immunofluorescence and Western blot analysis was performed for protein detection. RESULTS: YAP was stronger expressed in HCT-8/T than in HCT-8, and PTX resistance was positively correlated with the level of YAP expression. VP, a strongly YAP inhibitor, could reduce the PTX resistance on HCT-8/T cells without light activation by inhibiting YAP. Beside, VP and PTX combination therapy showed synergism on inhibition of YAP and cytotoxicity to HCT-8/T. Moreover, verteporfin and PTX combination therapy affect the invasion and colony formation ability and induce apoptosis of HCT-8/T cells. CONCLUSIONS: VP can reverse the PTX resistance induced by YAP over-expression in HCT-8/T cells without photoactivation through inhibiting YAP expression.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Paclitaxel/farmacologia , Fosfoproteínas/metabolismo , Porfirinas/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Humanos , Concentração Inibidora 50 , Microscopia Confocal , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/genética , Fármacos Fotossensibilizantes/farmacologia , Interferência de RNA , Fatores de Transcrição , Verteporfina , Proteínas de Sinalização YAPRESUMO
B-cell activating factor (BAFF) is involved in not only physiology of normal B cells, but also pathophysiology of aggressive B cells related to malignant and autoimmune diseases. Rapamycin, a lipophilic macrolide antibiotic, has recently shown to be effective in the treatment of human lupus erythematosus. However, how rapamycin inhibits BAFF-stimulated B-cell proliferation and survival has not been fully elucidated. Here, we show that rapamycin inhibited human soluble BAFF (hsBAFF)-induced cell proliferation and survival in normal and B-lymphoid (Raji and Daudi) cells by activation of PP2A and inactivation of Erk1/2. Pretreatment with PD98059, down-regulation of Erk1/2, expression of dominant negative MKK1, or overexpression of wild-type PP2A potentiated rapamycin's suppression of hsBAFF-activated Erk1/2 and B-cell proliferation/viability, whereas expression of constitutively active MKK1, inhibition of PP2A by okadaic acid, or expression of dominant negative PP2A attenuated the inhibitory effects of rapamycin. Furthermore, expression of a rapamycin-resistant and kinase-active mTOR (mTOR-T), but not a rapamycin-resistant and kinase-dead mTOR-T (mTOR-TE), conferred resistance to rapamycin's effects on PP2A, Erk1/2 and B-cell proliferation/viability, implying mTOR-dependent mechanism involved. The findings indicate that rapamycin inhibits BAFF-stimulated cell proliferation/survival by targeting mTOR-mediated PP2A-Erk1/2 signaling pathway in normal and neoplastic B-lymphoid cells. Our data highlight that rapamycin may be exploited for preventing excessive BAFF-induced aggressive B-cell malignancies and autoimmune diseases.