Enolase 1 stimulates glycolysis to promote chemoresistance in gastric cancer.
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ABSTRACT:
SUBMITTER: Qian X
PROVIDER: S-EPMC5564598 | biostudies-other | 2017 Jul
REPOSITORIES: biostudies-other
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Project description:There is increasing evidence that hexokinase is involved in cell proliferation and migration. However, the function of the hexokinase domain containing protein-1 (HKDC1) in gastric cancer (GC) remains unclear. Immunohistochemistry analysis and big data mining were used to evaluate the correlation between HKDC1 expression and clinical features in GC. In addition, the biological function and molecular mechanism of HKDC1 in GC were studied by in vitro and in vivo assays. Our study indicated that HKDC1 expression was upregulated in GC tissues compared with adjacent nontumor tissues. High expression of HKDC1 was associated with worse prognosis. Functional experiments demonstrated that HKDC1 upregulation promoted glycolysis, cell proliferation, and tumorigenesis. In addition, HKDC1 could enhance GC invasion and metastasis by inducing epithelial-mesenchymal transition (EMT). Abrogation of HKDC1 could effectively attenuate its oncogenic and metastatic function. Moreover, HKDC1 promoted GC proliferation and migration in vivo. HKDC1 overexpression conferred chemoresistance to cisplatin, oxaliplatin, and 5-fluorouracil (5-Fu) onto GC cells. Furthermore, nuclear factor kappa-B (NF-κB) inhibitor PS-341 could attenuate tumorigenesis, metastasis, and drug resistance ability induced by HKDC1 overexpression in GC cells. Our results highlight a critical role of HKDC1 in promoting glycolysis, tumorigenesis, and EMT of GC cells via activating the NF-κB pathway. In addition, HKDC1-mediated drug resistance was associated with DNA damage repair, which further activated NF-κB signaling. HKDC1 upregulation may be used as a potential indicator for choosing an effective chemotherapy regimen for GC patients undergoing chemotherapy.
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Project description:BackgroundReprogrammed energy metabolism has become an emerging hallmark of cancer in recent years. Transporters have been reported to be amino acid sensors involved in controlling mTOR recruitment and activation, which is crucial for the growth of both normal and tumor cells. L-type amino acid transporter 2 (LAT2), encoded by the SLC7A8 gene, is a Na+-independent neutral amino acid transporter and is responsible for transporting neutral amino acids, including glutamine, which can activate mTOR. Previous studies have shown that LAT2 was overexpressed in gemcitabine-resistant pancreatic cancer cells. However, the role of LAT2 in chemoresistance in pancreatic cancer remains uncertain and elusive.MethodsThe effects of LAT2 on biological behaviors were analyzed. LAT2 and LDHB levels in tissues were detected, and the clinical value was evaluated.ResultsWe demonstrated that LAT2 emerged as an oncogenic protein and could decrease the gemcitabine sensitivity of pancreatic cancer cells in vitro and in vivo. The results of a survival analysis indicated that high expression levels of both LAT2 and LDHB predicted a poor prognosis in patients with pancreatic cancer. Furthermore, we found that LAT2 could promote proliferation, inhibit apoptosis, activate glycolysis and alter glutamine metabolism to activate mTOR in vitro and in vivo. Next, we found that gemcitabine combined with an mTOR inhibitor (RAD001) could reverse the decrease in chemosensitivity caused by LAT2 overexpression in pancreatic cancer cells. Mechanistically, we demonstrated that LAT2 could regulate two glutamine-dependent positive feedback loops (the LAT2/p-mTORSer2448 loop and the glutamine/p-mTORSer2448/glutamine synthetase loop) to promote glycolysis and decrease gemcitabine (GEM) sensitivity in pancreatic cancer.ConclusionTaken together, our data reveal that LAT2 functions as an oncogenic protein and could regulate glutamine-dependent mTOR activation to promote glycolysis and decrease GEM sensitivity in pancreatic cancer. The LAT2-mTOR-LDHB pathway might be a promising therapeutic target in pancreatic cancer.
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Project description:Chemotherapy is one of the most important approaches for the treatment of various cancers. However, tumor cells often develop resistance to chemotherapeutic drugs. The tumor microenvironment reconstituted by various cytokines secreted from immune cells was recently found to play important roles in affecting therapeutic response of tumor cells. Herein, we reported that tumor cells can secrete autocrine cytokines to confer chemoresistance by inactivating proapoptotic autophagy. Through cytokine screening, we found that drug resistant cancer cells secreted more CCL2 than drug sensitive cells. Such secreted CCL2 could not only maintain chemoresistance in drug-resistant cancer cells but also confer drug resistance to drug-sensitive cancer cells. CCL2 attenuated drug-induced cytotoxicity by activating PI3K-Akt-mTOR signaling to inhibit proapoptotic autophagy and increase SQSTM1 expression. CCL2 expression in primary carcinoma tissues also correlated well with SQSTM1 expression. Either CCL2 knock-down or autophagy induction successfully reversed drug resistance of tumor cells. Moreover, increased expression of SQSTM1 in turn activated CCL2 transcription via NF-?B signal pathway, representing a positive feedback loop to maintain drug resistance. Therefore, our results provided a new insight to understand drug resistance, and indicated the potential value of CCL2 as a biomarker and intervention target for chemotherapy resistance.
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Project description:Ovarian cancer (OvCa), while accounting for only 3% of all women's cancer, is the fifth leading cause of cancer death among women. One of the most significant obstacles to successful OvCa treatment is chemoresistance. The current lack of understanding of the driving mechanisms underlying chemoresistance hinders the development of effective therapeutics against this obstacle. Adipocytes are key components of the OvCa microenvironment and have been shown to be involved in OvCa cell proliferation, however, little is known about their impact on OvCa chemoresistance. In the current study, we found that adipocytes, of both subcutaneous and visceral origin, secrete factors that enhance the resistance of OvCa cells against chemotherapeutic drugs by activating the Akt pathway. Importantly, we have demonstrated that secreted lipids mediate adipocyte-induced chemoresistance. Through a comprehensive lipidomic analysis, we have identified this chemo-protective lipid mediator as arachidonic acid (AA). AA acts on OvCa cells directly, not through its downstream derivatives such as prostaglandins, to activate Akt and inhibit cisplatin-induced apoptosis. Taken together, our study has identified adipocytes and their secreted AA as important mediators of OvCa chemoresistance. Strategies that block the production of AA from adipocytes or block its anti-apoptotic function may potentially inhibit chemoresistance in OvCa patients.
| S-EPMC6746782 | biostudies-literature
Project description:Growing tumors alter their metabolic profiles to support the increased cell proliferation. SETD1A, a histone lysine methyltransferase which specifically methylates H3K4, plays important roles in both normal cell and cancer cell functions. However, the function of SETD1A in gastric cancer (GC) progression and its role in GC metabolic reprogramming are still largely unknown. In the current study, we discovered that the expression of SETD1A was higher in GC tumor specimens compared to surrounding nontumor tissues. Upregulation of SETD1A increased GC cell proliferation, whereas downregulation of SETD1A inhibited GC cell proliferation. Furthermore, knockdown of SETD1A reduced glucose uptake and production of lactate and suppressed glycolysis by decreasing the expression of glycolytic genes, including GLUT1, HK2, PFK2, PKM2, LDHA, and MCT4. Mechanistically, SETD1A interacted with HIF1α to strengthen its transactivation, indicating that SETD1A promotes glycolysis through coactivation of HIF1α. SETD1A and HIF1α were recruited to the promoter of HK2 and PFK2, where SETD1A could methylate H3K4. However, knockdown of SETD1A decreased the methylation of H3K4 on HK2 and PFK2 promoter and reduced HIF1α recruitment necessary to promote transcription of glycolytic genes. Inhibition of HIF1α decelerated SETD1A-enhanced GC cell growth. In additional, there was a linear correlation between SETD1A and several key glycolytic genes in human GC specimens obtained from TCGA dataset. Thus, our results demonstrated that SETD1A interacted with HIF1α to promote glycolysis and accelerate GC progression, implicating that SETD1A may be a potential molecular target for GC treatment.
| S-EPMC7266269 | biostudies-literature
Project description:The incidence of lung cancer is increasing worldwide. Although great progress in lung cancer treatment has been made, the clinical outcome is still unsatisfactory. Tripartite motif (TRIM)-containing proteins has been shown to be closely related to tumor progression. However, the function of TRIM46 in lung cancer is largely unknown. Here, TRIM46 amplification was found in lung adenocarcinoma (LUAD) tissues and TRIM46 amplification was significantly associated with a poor survival rate. Overexpression of wild type TRIM46 increased the proliferation of LUAD cells and glycolysis, promoted xenografts growth, and enhanced cisplatin (DDP) resistance of LUAD cells via increased ubiquitination of pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) and upregulation of p-AKT. In contrast, overexpression of RING-mutant TRIM46 did not show any effects, suggesting the function of TRIM46 was dependent on the E3 ligase activity. Furthermore, we found that TRIM46 promoted LUAD cell proliferation and DDP resistance by enhancing glycolysis. PHLPP2 overexpression reversed the effects of TRIM46 overexpression. Amplification of TRIM46 also promoted LUAD growth and enhanced its DDP resistance in a patient-derived xenograft (PDX) model. In conclusion, our data highlight the importance of TRIM46/PHLPP2/AKT signaling in lung cancer and provide new insights into therapeutic strategies for lung cancer.
| S-EPMC8967906 | biostudies-literature
Project description:BackgroundGastric cancer (GC) is one of the most common types of cancer worldwide, which leads to more than 10% of cancer-related deaths. Metabolism reprogramming presents as a pivotal event in cancer initiation and progression through enhancing aerobic glycolysis and anabolic metabolism. However, the underlying regulatory mechanisms in GC remain unknown.MethodsVAL was identified by bioinformatics analyses in GC. Cell-based assays and mouse model illustrate the role of VAL in GC. RNA pull-down, immunoprecipitation assay and Western blot elucidate the interaction between VAL and PKM2. Pyruvate kinase activity, ECAR and OCR were measured to validate aerobic glycolysis of GC cells.ResultsLong non-coding RNA (lncRNA) VAL is significantly upregulated in GCs and indicates poor prognosis. Functional assays showed that VAL promotes GC malignant progression. Mechanistically, VAL strengthens the enzymatic activity of PKM2 and aerobic glycolysis of GC cells through directly binding with PKM2 to abrogate the PKM2-Parkin interaction, and to suppress Parkin-induced polyubiquitination of PKM2. In addition, glucose starvation induces VAL expression to enhance this process.ConclusionsOur study provides an insight into an lncRNA-dependent regulation on the enzymatic activity of PKM2, and suggests a potential of targeting VAL or PKM2 as promising biomarkers in GC diagnosis and treatment.
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Project description:Caveolin 1 (Cav-1) is a plasma membrane-associated protein with the capacity to modulate signaling activities in a context-dependent fashion. Interactions between Cav-1 and low-density lipoprotein receptor-related protein 6 (LRP6) were reported to be important for the regulation of Wnt-?-catenin (?-cat) signaling. Cav-1 also interacts with insulin and IGF-I receptors (IGF-IR/IR) and can stimulate IR kinase activities. We found positive correlation between Cav-1 and LRP6 expression in both human primary prostate cancer and metastasis tissues and in PC-3 cells. Cav-1 stimulation of Wnt-?-cat signaling and c-Myc levels was positively associated with LRP6 expression in LNCaP, PC-3, and DU145 prostate cancer cells. Importantly, LRP6 and, to a lesser extent, Cav-1 were found to stimulate aerobic glycolysis. These activities were positively associated with the expression of HK2 and Glut3 and shown to be dependent on Akt signaling by both gene knockdown and chemical inhibition methods. We further showed that Cav-1 and LRP6 exert their effects on Akt and glycolytic activities by stimulating IGF-IR/IR signaling. Overall, our results show that Cav-1 interacts with LRP6 to generate an integrated signaling module that leads to the activation of IGF-IR/IR and results in stimulation of Akt-mTORC1 signaling and aerobic glycolysis in prostate cancer.
| S-EPMC3688259 | biostudies-literature
Project description:BackgroundWe previously reported an inverse relationship between B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and Raf kinase inhibitory protein (RKIP), which is associated with the prognosis of gastric cancer (GC). In this study, we further explored the microRNA (miRNA) regulatory mechanism between Bmi-1 and RKIP.MethodsMicroarray analysis was first carried out to identify miRNA profiles that were differentially expressed in cells overexpressing Bmi-1. Then, miRNAs that could regulate RKIP were identified. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to measure the expression of Bmi-1, miR-155, miR-27a and RKIP. RKIP was confirmed as a target of miR-27a and miR-155 through luciferase reporter assays, qRT-PCR and Western blotting. The effects of the Bmi-1/miR-27a/RKIP and Bmi-1/miR-155/RKIP axes on tumor growth, proliferation, migration, invasion, colony-formation ability, metastasis and chemoresistance were investigated both in vitro and in vivo.ResultsThe downregulation of RKIP by Bmi-1 occurred at the protein but not mRNA level. This indicates probable posttranscriptional regulation. miRNA expression profiles of cells with ectopic expression of Bmi-1 were analyzed and compared to those of control cells by microarray analysis. A total of 51 upregulated and 72 downregulated miRNAs were identified. Based on publicly available algorithms, miR-27a and miR-155 were predicted, selected and demonstrated to target RKIP. Bmi-1, miR-27a and miR-155 are elevated in human GC and associated with poor prognosis of GC, while RKIP is expressed at lower levels in GC and correlated with good prognosis. Then, in vitro tests shown that in addition to regulating RKIP expression via miR-27a and miR-155, Bmi-1 was also able to regulate the migration, invasion, proliferation, colony-formation ability and chemosensitivity of GC cells through the same pathway. Finally, the in vivo test showed similar results, whereby the knockdown of the Bmi-1 gene led to the inhibition of tumor growth, metastasis and chemoresistance through miR-27a and miR-155.ConclusionsBmi-1 was proven to induce the expression of miR-27a and miR-155 and thus promote tumor metastasis and chemoresistance by targeting RKIP in GC. Overall, miR-27a and miR-155 might be promising targets for the screening, diagnosis, prognosis, treatment and disease monitoring of GC.
| S-EPMC7315508 | biostudies-literature