scholarly journals Hypoxia induces sorafenib resistance mediated by autophagy via activating FOXO3a in hepatocellular carcinoma

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Chao Liang ◽  
Zhebin Dong ◽  
Xianlei Cai ◽  
Jie Shen ◽  
Yuan Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Term Therapy ◽  
Advanced Hepatocellular Carcinoma ◽  
Multikinase Inhibitor ◽  
Sorafenib Treatment ◽  
Clinical Prognosis ◽  
Nuclear Location ◽  
Long Term Therapy ◽  
Hcc Cells

AbstractSorafenib, a multikinase inhibitor, is considered as the only approved drug to cure the advanced hepatocellular carcinoma (HCC); however, the acquired chemoresistance caused by intratumoral hypoxia through sorafenib long term therapy induces sorafenib inefficacy. We demonstrated here that hypoxia significantly attenuated sensitivity of HCC cells to sorafenib treatment and reduced its proliferation. Autophagy was observed in sorafenib-treated HCC cells in hypoxia, and inhibition of autophagy by 3-MA eliminated hypoxia-induced sorafenib resistance. Further study revealed hypoxia-activated FOXO3a, an important cellular stress transcriptional factor, via inducing its dephosphorylation and nuclear location; and FOXO3a-dependent transcriptive activation of beclin-1 was responsible for hypoxia-induced autophagy in HCC cells. Knockout of FOXO3a inhibited the autophagy induced by sorafenib itself in normoxia and significantly enhanced the cytotoxicity of sorafenib in HCC cells; and it also inhibited the hypoxia-induced autophagy and achieved the same effect in sorafenib sensitivity-enhancement in HCC cells as it in normoxia. Finally, knockout of intratumoral FOXO3a significantly enhanced curative efficacy of sorafenib via inhibition of autophagy in xenograft tumors in nude mice. Collectively, our study suggests that FOXO3a plays a key role in regulating hypoxia-induced autophagy in sorafenib-treated HCC, and FOXO3-targeted therapy may serve as a promising approach to improve clinical prognosis of patients suffering from HCC.

scholarly journals MiRNA-124-3p.1 sensitizes hepatocellular carcinoma cells to sorafenib by regulating FOXO3a by targeting AKT2 and SIRT1

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Zhe-bin Dong ◽  
Heng-miao Wu ◽  
Yi-cheng He ◽  
Zhong-ting Huang ◽  
Yi-hui Weng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Acquired Resistance ◽  
Xenograft Model ◽  
Early Recurrence ◽  
Advanced Hepatocellular Carcinoma ◽  
Curative Surgery ◽  
Multikinase Inhibitor ◽  
Key Factor ◽  
Nuclear Location ◽  
Induced Apoptosis

AbstractAs a multikinase inhibitor, sorafenib is commonly used to treat patients with advanced hepatocellular carcinoma (HCC), however, acquired resistance to sorafenib is a major obstacle to the effectiveness of this treatment. Thus, in this study, we investigated the mechanisms underlying sorafenib resistance as well as approaches devised to increase the sensitivity of HCC to sorafenib. We demonstrated that miR-124-3p.1 downregulation is associated with early recurrence in HCC patients who underwent curative surgery and sorafenib resistance in HCC cell lines. Regarding the mechanism of this phenomenon, we identified FOXO3a, an important cellular stress transcriptional factor, as the key factor in the function of miR-124-3p.1 in HCC. We showed that miR-124-3p.1 binds directly to AKT2 and SIRT1 to reduce the levels of these proteins. Furthermore, we showed that AKT2 and SIRT1 phosphorylate and deacetylate FOXO3a. We also found that miR-124-3p.1 maintains the dephosphorylation and acetylation of FOXO3a, leading to the nuclear location of FOXO3a and enhanced sorafenib-induced apoptosis. Moreover, the combination of miR-124-3p.1 mimics and sorafenib significantly enhanced the curative efficacy of sorafenib in a nude mouse HCC xenograft model. Collectively, our data reveal that miR-124-3p.1 represents a predictive indicator of early recurrence and sorafenib sensitivity in HCC. Furthermore, we demonstrate that miR-124-3p.1 enhances the curative efficacy of sorafenib through dual effects on FOXO3a. Thus, the miR-124-3p.1-FOXO3a axis is implicated as a potential target for the diagnosis and treatment of HCC.

Wild type Kirsten rat sarcoma is a novel microRNA-622-regulated therapeutic target for hepatocellular carcinoma and contributes to sorafenib resistance

Gut ◽  
2017 ◽  
Vol 67 (7) ◽  
pp. 1328-1341 ◽  
Author(s):  
Peter Dietrich ◽  
Andreas Koch ◽  
Valerie Fritz ◽  
Arndt Hartmann ◽  
Anja Katrin Bosserhoff ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Functional Analysis ◽  
Protein Kinase ◽  
Advanced Hepatocellular Carcinoma ◽  
Wild Type ◽  
Sorafenib Treatment ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Hcc Cells

ObjectiveSorafenib is the only effective therapy for advanced hepatocellular carcinoma (HCC). Combinatory approaches targeting mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)- and phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)/protein-kinase B(AKT) signalling yield major therapeutic improvements. RAS proteins regulate both RAF/MAPK and PI3K/AKT signalling. However, the most important RAS isoform in carcinogenesis, Kirsten rat sarcoma (KRAS), remains unexplored in HCC.DesignHuman HCC tissues and cell lines were used for expression and functional analysis. Sorafenib-resistant HCC cells were newly generated. RNA interference and the novel small molecule deltarasin were used for KRAS inhibition both in vitro and in a murine syngeneic orthotopic HCC model.ResultsExpression of wild type KRAS messenger RNA and protein was increased in HCC and correlated with extracellular-signal regulated kinase (ERK) activation, proliferation rate, advanced tumour size and poor patient survival. Bioinformatic analysis and reporter assays revealed that KRAS is a direct target of microRNA-622. This microRNA was downregulated in HCC, and functional analysis demonstrated that KRAS-suppression is the major mediator of its inhibitory effect on HCC proliferation. KRAS inhibition markedly suppressed RAF/ERK and PI3K/AKT signalling and proliferation and enhanced apoptosis of HCC cells in vitro and in vivo. Combinatory KRAS inhibition and sorafenib treatment revealed synergistic antitumorigenic effects in HCC. Sorafenib-resistant HCC cells showed elevated KRAS expression, and KRAS inhibition resensitised sorafenib-resistant cells to suppression of proliferation and induction of apoptosis.ConclusionsKRAS is dysregulated in HCC by loss of tumour-suppressive microRNA-622, contributing to tumour progression, sorafenib sensitivity and resistance. KRAS inhibition alone or in combination with sorafenib appears as novel promising therapeutic strategy for HCC.

scholarly journals CISD2 Promotes Resistance to Sorafenib-Induced Ferroptosis by Regulating Autophagy in Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Bowen Li ◽  
Shibo Wei ◽  
Liang Yang ◽  
Xueqiang Peng ◽  
Yingbo Ma ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
Kinase Inhibitor ◽  
Bioinformatic Analysis ◽  
Advanced Hepatocellular Carcinoma ◽  
Iron Ions ◽  
Sorafenib Treatment ◽  
Effective Therapeutic Strategy ◽  
Detect Gene Expression ◽  
Hcc Cells

PurposeSorafenib is a multi-kinase inhibitor that is used as a standard treatment for advanced hepatocellular carcinoma (HCC). However, the mechanism of sorafenib resistance in HCC is still unclear. It has been shown that CISD2 expression is related to the progression and poor prognosis of HCC. Here, we show a new role for CISD2 in sorafenib resistance in HCC.MethodsBioinformatic analysis was used to detect the expression of negative regulatory genes of ferroptosis in sorafenib-resistant samples. The concentration gradient method was used to establish sorafenib-resistant HCC cells. Western blot was used to detect the protein expression of CISD2, LC3, ERK, PI3K, AKT, mTOR, and Beclin1 in HCC samples. Quantitative real-time PCR (qPCR) was used to detect gene expression. CISD2 shRNA and Beclin1 shRNA were transfected to knock down the expression of the corresponding genes. Cell viability was detected by a CCK-8 assay. ROS were detected by DCFH-DA staining, and MDA and GSH were detected with a Lipid Peroxidation MDA Assay Kit and Micro Reduced Glutathione (GSH) Assay Kit, respectively. Flow cytometry was used to detect apoptosis and the levels of ROS and iron ions.ResultsCISD2 was highly expressed in HCC cells compared with normal cells and was associated with poor prognosis in patients. Knockdown of CISD2 promoted a decrease in the viability of drug-resistant HCC cells. CISD2 knockdown promoted sorafenib-induced ferroptosis in resistant HCC cells. The levels of ROS, MDA, and iron ions increased, but the change in GSH was not obvious. Knockdown of CISD2 promoted uncontrolled autophagy in resistant HCC cells. Inhibition of autophagy attenuated CISD2 knockdown-induced ferroptosis. The autophagy promoted by CISD2 knockdown was related to Beclin1. When CISD2 and Beclin1 were inhibited, the effect on ferroptosis was correspondingly weakened.ConclusionInhibition of CISD2 promoted sorafenib-induced ferroptosis in resistant cells, and this process promoted excessive iron ion accumulation through autophagy, leading to ferroptosis. The combination of CISD2 inhibition and sorafenib treatment is an effective therapeutic strategy for resistant HCC.

Antithrombotic Therapy for DVT/PE

1997 ◽  
Vol 17 (03) ◽  
pp. 161-162
Author(s):  
Thomas Hyers
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Oral Anticoagulants ◽  
Cost Effective ◽  
Therapeutic Agents ◽  
Great Promise ◽  
Term Therapy ◽  
Low Molecular Weight ◽  
Long Term Therapy

SummaryProblems with unfractionated heparin as an antithrombotic have led to the development of new therapeutic agents. Of these, low molecular weight heparin shows great promise and has led to out-patient therapy of DVT/PE in selected patients. Oral anticoagulants remain the choice for long-term therapy. More cost-effective ways to give oral anticoagulants are needed.

Office-based post-marketing surveillance study on the influence of long term therapy with aripiprazole in patients with schizophrenia

2007 ◽  
Vol 40 (05) ◽  
Author(s):  
M Kungel ◽  
A Engelhardt ◽  
T Spevakné-Göröcs ◽  
M Ebrecht ◽  
C Werner ◽  
...  
Keyword(s):  
Surveillance Study ◽  
Term Therapy ◽  
Post Marketing Surveillance ◽  
Post Marketing ◽  
Long Term Therapy
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