Targeting mTORC1/2 Complexes Inhibit Tumorigenesis and Enhance Sensitivity to 5-Flourouracil (5-FU) in Hepatocellular Carcinoma: A Preclinical Study of mTORC1/2-Targeted Therapy in Hepatocellular Carcinoma (HCC)

Zhang, Yu; Jia, Qingan; Kadel, Dhruba; Zhang, Xiaofei; Zhang, Quanbao

doi:10.12659/msm.907514

Cited by 18 publications

(11 citation statements)

References 24 publications

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“…Additionally, using tissues and cells from patients with papillary thyroid cancer, an altered overexpression of glutaminase was observed. When GLS was inhibited using a siRNA, mTORC1-signaling pathway was deactivated leading to an increase of autophagy and apoptosis (160).…”

Section: Glutaminolysis and Mtorc1 In Cancermentioning

confidence: 99%

“…Rapamycin is the first known allosteric mTORC1 inhibitor studied, however, its poor water solubility and chemical stability have led to implement instead the use of semi-synthetic rapamycin analogs (or rapalogs) that show improved pharmacokinetic properties, solubility and reduced immunosuppressive effects (159,160). To date, three rapalogs are being tested in clinical trials, CCI-779 (temsirolimus), AP23573 or MK-8669 (ridaforolimus), and RAD001 (everolimus) (198).…”

Section: Mtorc1 As a Therapeutic Targetmentioning

confidence: 99%

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mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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Continuous proliferation of tumor cells requires constant adaptations of energy metabolism to rapidly fuel cell growth and division. This energetic adaptation often comprises deregulated glucose uptake and lactate production in the presence of oxygen, a process known as the "Warburg effect." For many years it was thought that the Warburg effect was a result of mitochondrial damage, however, unlike this proposal tumor cell mitochondria maintain their functionality, and is essential for integrating a variety of signals and adapting the metabolic activity of the tumor cell. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of numerous cellular processes implicated in proliferation, metabolism, and cell growth. mTORC1 controls cellular metabolism mainly by regulating the translation and transcription of metabolic genes, such as peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1α), sterol regulatory element-binding protein 1/2 (SREBP1/2), and hypoxia inducible factor-1 α (HIF-1α). Interestingly it has been shown that mTORC1 regulates mitochondrial metabolism, thus representing an important regulator in mitochondrial function. Here we present an overview on the role of mTORC1 in the regulation of mitochondrial functions in cancer, considering new evidences showing that mTORC1 regulates the translation of nucleus-encoded mitochondrial mRNAs that result in an increased ATP mitochondrial production. Moreover, we discuss the relationship between mTORC1 and glutaminolysis, as well as mitochondrial metabolites. In addition, mitochondrial fission processes regulated by mTORC1 and its impact on cancer are discussed. Finally, we also review the therapeutic efficacy of mTORC1 inhibitors in cancer treatments, considering its use in combination with other drugs, with particular focus on cellular metabolism inhibitors, that could help improve their anti neoplastic effect and eliminate cancer cells in patients. de la Cruz López et al. mTORC1 and Mitochondrial Functions Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a shared affiliation, though no other collaboration, with with several of the authors AG and KC.

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Section: Glutaminolysis and Mtorc1 In Cancermentioning

confidence: 99%

Section: Mtorc1 As a Therapeutic Targetmentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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“…Currently, some studies have reported that TSC2 could be a therapeutic target in HCC. 9–11 However, the value of TSC2 in predicting the prognosis after hepatectomy was rarely reported. In this study, we aimed to detect the genomic variations (GAs) of HCC and evaluated the potential value of TSC2 in predicting the prognosis of HCC patients after hepatectomy.…”

Section: Introductionmentioning

confidence: 99%

TSC2 Mutations Were Associated with the Early Recurrence of Patients with HCC Underwent Hepatectomy

Song

Yang

et al. 2021

PGPM

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Purpose To explore the value of Tuberous sclerosis complex 2 ( TSC2 ) mutations in evaluating the early recurrence of hepatocellular carcinoma (HCC) patients underwent hepatectomy. Patients and Methods A total of 183 HCC patients were enrolled. Next-generation sequencing was performed on tumor tissues to analyze genomic alterations, tumor mutational burden and variant allele fraction (VAF). The associations between TSC2 mutations and recurrence rate within 1 year, RFS and OS after hepatectomy were analyzed. Results Our results showed that TSC2 mutation frequency in HCC was 12.6%. Compared to patients without TSC2 mutation, the proportion of microvascular invasion (MVI) and Edmondson grade III–IV was significantly higher in patients with a TSC2 mutation (p<0.05). The VAF of mutated TSC2 was higher in patients with maximum diameter of tumor >5cm or MVI than that of other patients (p<0.05). The frequency of TP53 mutation was significantly higher in patients with a TSC2 mutation than those without TSC2 mutation (p=0.003). Follow-up analysis showed that patients with a TSC2 mutation had significantly higher recurrence rate within 1 year ( p =0.015) and poorer median recurrence-free survival (RFS) ( p =0.010) than patients without TSC2 mutation. TSC2 mutations did not significantly affect overall survival of patients ( p =0.480). The multivariate analysis results showed that the Barcelona Clinic Liver Cancer (BCLC) B-C stage, TSC2 mutations and preoperative serum alpha-fetoprotein level ≥400μg/L were independently associated with recurrence within 1 year after hepatectomy (HR=8.628, 95% CI: 3.836–19.405, p =0.000; HR=3.885, 95% CI: 1.295–11.653, p =0.015; HR=2.327, 95% CI: 1.018–5.323, p =0.045; respectively), and poorer RFS after hepatectomy (HR=3.070, 95% CI: 1.971–4.783, p =0.000; HR=1.861, 95% CI: 1.061–3.267, p =0.030; HR=1.715, 95% CI: 1.093–2.693, p =0.019; respectively). Conclusion TSC2 mutations were significantly associated with MVI in liver para-carcinoma tissue and Edmondson grade III–IV in patients with HCC and were independently associated with recurrence within 1 year and poorer RFS after hepatectomy. The TSC2 mutation may be a potential predictor for early recurrence in HCC patients underwent hepatectomy.

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“…1 Hepatocarcinogenesis is associated with multiple etiological factors, such as alcohol abuse, epigenetic alterations, hepatitis cirrhosis, and virus infection. [2][3][4] Till now, surgical resection and liver transplantation are still the preferred and effective therapies for early stage of HCC patients, but the recurrence rate is >65%. 5,6 In addition, most patients are diagnosed at advanced stage that vitiates the therapeutic outcomes.…”

Section: Introductionmentioning

confidence: 99%

Retracted: Long Noncoding RNA HOTAIR Contributes to Progression in Hepatocellular Carcinoma by Sponging miR-217-5p

Gong

Zhu

2020

Cancer Biotherapy and Radiopharmaceuticals

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Background: Hepatocellular carcinoma (HCC) is an aggressive primary hepatic cancer with high malignancy and poor prognosis. Long noncoding RNA HOTAIR has been classified as an oncogene to accelerate cell proliferation, migration, and invasion in many cancer types by interacting with the miRNA. Therefore, we assumed that HOTAIR might participate in HCC cell progression by interacting with miR-217-5p expression. Materials and Methods: The expression of HOTAIR and miR-217-5p in 35 HCC patients and HCC cells was measured by quantitative real-time polymerase chain reaction. Cell transfection was conducted using Lipofectamine 2000 transfection reagent. CCK8 and flow cytometry was applied for the measurement of cell proliferation and apoptosis. Cell migration and invasion capacities were carried out by transwell assay. Xenograft mice were constructed by subcutaneously injecting of stably transfected Huh-7 cells in mice. The interaction between HOTAIR and miR-217-5p was determined by luciferase reporter system. Protein expression of P13K, p-P13K, AKT, p-AKT, MMP-2, and MMP-9 was analyzed using Western blot assay. Results: The expression of HOTAIR was upregulated, whereas miR-217-5p was downregulated in HCC tumor tissues and cell lines (Hep3B and Huh-7) compared with normal tissues and human normal liver cell line MIHA. In addition, HOTAIR expression was negatively correlated with miR-217-5p expression in HCC (r 2 = 0.1867, p = 0.0171). More importantly, HOTAIR knockdown induced apoptosis and inhibited cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). In vivo experiments revealed that the interference of HOTAIR inhibited tumor growth. Subsequently, luciferase reporter system confirmed the interaction between HOTAIR and miR-217-5p. The rescue experiments clarified that miR-217-5p inhibitor attenuated the suppression of HOTAIR silencing on HCC cell proliferation, migration, invasion, and EMT. Furthermore, miR-217-5p inhibitor restored the inhibition of HOTAIR silencing mediated p-PI3K/p-AKT/ MMP-2/9 protein expression. Conclusions: HOTAIR contributes to cell progression in HCC by sponging miR-217-5p, representing promising biomarkers for HCC treatment.

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Targeting mTORC1/2 Complexes Inhibit Tumorigenesis and Enhance Sensitivity to 5-Flourouracil (5-FU) in Hepatocellular Carcinoma: A Preclinical Study of mTORC1/2-Targeted Therapy in Hepatocellular Carcinoma (HCC)

Cited by 18 publications

References 24 publications

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

TSC2 Mutations Were Associated with the Early Recurrence of Patients with HCC Underwent Hepatectomy

Retracted: Long Noncoding RNA HOTAIR Contributes to Progression in Hepatocellular Carcinoma by Sponging miR-217-5p

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