A novel heat shock protein inhibitor KU757 with efficacy in lenvatinib-resistant follicular thyroid cancer cells overcomes up-regulated glycolysis in drug-resistant cells in vitro

Subramanian, Chitra; Gorney, Rebecca M.; Ton, Wang; Ge, Derek; Zhang, Nina; Zuo, Ang; Blagg, Brian S. J.; Cohen, Mark S.

doi:10.1016/j.surg.2020.06.009

Cited by 10 publications

(6 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Resistance to lenvatinib increases glycolysis [ 16 ], thus we wanted to assess the effect of NOX4 on glycolysis in LRBCs. The measurements of the extracellular acidification rate (ECAR) showed that LRBCs have a higher glycolytic capacity than the parent cells, but the increment can be dropped close to the level caused by shNOX4 in the parent cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Lenvatinib can suppress DTC albeit existence of adverse events [ 41 ], but tumor cells developed resistant mechanisms that involved alternative pathways for survival [ 42 ]. Metabolically, lenvatinib resistance leads to increased glycolysis [ 16 ], so overcoming this increase would be a potential strategy to solve the resistance. Previously we reported that NOX4 serves as a glycolytic regulator via ROS in hypoxia [ 10 ], the present study demonstrated not only the supportive effect of NOX4 on lenvatinib-induced glycolysis under serum-starved conditions via ROS in PTC cells in vitro, but also the surprising effect upon combinatory treatment of GLX351322 and lenvatinib in vivo, suggesting that PTC cells depend on NOX4 or NOX4-derived ROS to establish plasticity that is capable of responding to complex and changeable tumor microenvironments.…”

Section: Discussionmentioning

confidence: 99%

“…However, lenvatinib has no significant impact on improving the overall survival rate for this disease so almost 50% of patients with advance DTC treated with lenvatinib will develop significant disease progression after average of 18 months due to resistance mechanisms [ 15 – 17 ]. Importantly, lenvatinib could induce elevated ROS production [ 18 ], and resistance to lenvatinib leads to increased glycolysis [ 16 ]. Combining with the role of NOX4 in ROS and glycolysis in PTC [ 10 ], it still needs to be further investigated whether NOX4 is involved in the process of resistance to lenvatinib and how.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting NOX4 disrupts the resistance of papillary thyroid carcinoma to chemotherapeutic drugs and lenvatinib

et al. 2022

View full text Add to dashboard Cite

Advanced differentiated thyroid cancer cells are subjected to extreme nutritional starvation which contributes to develop resistance to treatments; however, the underlying mechanism remains unclear. Cells were subjected to serum deprivation by culture in medium containing 0.5% fetal bovine serum. A CCK8 assay, cell death Detection ELISAPLUS kit, and PI staining were conducted to determine cell viability, cell apoptosis, and cell cycle, respectively. NADPH oxidase 4 (NOX4) knockdown–stable cell lines were generated by lentivirus-mediated shRNA knockdown in BCPAP cells and TPC-1 cells. Etoposide and doxorubicin, two chemotherapeutic drugs, as well as lenvatinib were utilized to determine the effect of NOX4 on drug resistance. Lenvatinib-resistant BCPAP cells (LRBCs) were established to confirm this effect. The underlining mechanisms of NOX4 under starvation were explored using western blot. Finally, GLX351322, an inhibitor targeting NOX4, was used to inhibit NOX4-derived ROS in vitro and detect its effect on drug resistance of tumor cells in vivo. NOX4 is overexpressed under serum deprivation in BCPAP or TPC-1 cells. NOX4 knockdown impairs cell viability, increases cell apoptosis, extends G1 phase during cell cycle and modulates the level of energy-associated metabolites in starved cells. When the starved cells or LRBCs are treated with chemotherapeutic drugs or Lenvatinib, NOX4 knockdown inhibits cell viability and aggravates cell apoptosis depending on NOX4-derived ROS production. Mechanistically, starvation activates TGFβ1/SMAD3 signal, which mediates NOX4 upregulation. The upregulated NOX4 then triggers ERKs and PI3K/AKT pathway to influence cell apoptosis. GLX351322, a NOX4-derived ROS inhibitor, has an inhibitory effect on cell growth in vitro and the growth of BCPAP-derived even LRBCs-derived xenografts in vivo. These findings highlight NOX4 and NOX4-derived ROS as a potential therapeutic target in resistance to PTC.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting NOX4 disrupts the resistance of papillary thyroid carcinoma to chemotherapeutic drugs and lenvatinib

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Crouch et al 35 found that in breast cancer, ectopic HSP90 expression was the highest in glycolytic tumors, and HSP90 inhibition was more effective in glycolytic tumors. Subramanian et al 36 found that a novel C-terminal HSP90 inhibitor (KU757) can effectively treat lenvatinib-resistant cells by targeting glycolysis. Liu et al 37 reported that a class of inhibitors of the calcineurin-NFAT pathway (YZ129 and its derivatives) suppressed glycolysis by competitive binding with HSP90 in glioblastoma.…”

Section: Discussionmentioning

confidence: 99%

HSP90AB1 Promotes the Proliferation, Migration, and Glycolysis of Head and Neck Squamous Cell Carcinoma

Yin

Zhang

Zhou

et al. 2022

Technol Cancer Res Treat

View full text Add to dashboard Cite

Background: Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide. Heat shock protein 90 alpha family class B member 1 (HSP90AB1) is highly expressed in a variety of cancers and is associated with poor prognosis, however, its role in HNSCC is still poorly understood. This study aimed to explore the function HSP90AB1 played in HNSCC progression. Methods: The expression level of HSP90AB1 in HNSCC was analyzed by bioinformatics analysis and western blotting, and its relationship with clinicopathological parameters was analyzed by bioinformatics analysis and immunohistochemistry. Three stable HSP90AB1 knockdown HNSCC cell lines were constructed by lentiviral transfection. The effect of HSP90AB1 knockdown on the proliferation and migration of HNSCC cells was tested by CCK-8 assay, EdU incorporation assay, colony formation assay, nude mouse xenograft models, transwell migration assay, wound healing assay, and western blotting. The effect of HSP90AB1 knockdown on glycolysis in HNSCC cells was assessed by quantitative real-time PCR and related assay kits. Finally, the levels of Akt and phospho-Akt (Ser473) proteins after HSP90AB1 knockdown were detected by western blotting. Results: HSP90AB1 was highly expressed in HNSCC and associated with T grade, lymph node metastasis, and prognosis. Knockdown of HSP90AB1 inhibited the proliferation, migration, and glycolysis of HNSCC, and reduced the level of phospho-Akt. Conclusion: HSP90AB1 functions as an oncogene in HNSCC, and has the potential to become a prognostic factor and therapeutic target.

show abstract

“…Also known as HSPD1, HSP60 was found to be upregulated in myeloma cells, and silencing of HSP60 inhibited glycolysis (31). The novel C-terminal HSP90 inhibitor KU757 could overcome the increase in aerobic glycolysis induced by lenvatinib treatment in lenvatinib-resistant follicular thyroid cancer cells (32). In addition, hyper-activation of the β-catenin signaling plays an important role in the drug resistance of lung cancer (22,23), suggesting that DNAJC12 may participate in regulating the DDP resistance of lung cancer through activating the β-catenin signaling Moreover, evidence has demonstrated that aerobic glycolysis deregulation can help cancer cells to increase drug resistance.…”

Section: Discussionmentioning

confidence: 99%

DNAJC12 activated by HNF1A enhances aerobic glycolysis and drug resistance in non-small cell lung cancer

Wang¹,

Huang²,

Liu³

2022

Ann Transl Med

View full text Add to dashboard Cite

Background: The DnaJ heat shock protein family member C12 (DNAJC12) gene has been demonstrated to promote lung cancer cell growth and migration by increasing β-catenin expression. In this study, we aimed to reveal the role of DNAJC12 in modulating aerobic glycolysis and cisplatin (DDP) resistance in non-small cell lung cancer (NSCLC).Methods: Bioinformatics analysis was applied to assess the expression levels of DNAJC12 and hepatocyte nuclear factor 1-alpha (HNF1A) in NSCLC tissues and the correlation between DNAJC12 and HNF1A expression levels. Cell Counting Kit-8 (CCK-8), flow cytometry assay, and in vivo tumor formation were used to evaluate cell growth, apoptosis, and tumorigenesis. Luciferase gene reporter assay was adopted to assess the relationship between HNF1A and DNAJC12.Results: Both DNAJC12 and HNF1A were overexpressed in NSCLC tissues and cells, and their expressions showed a positive correlation. The HNF1A gene could bind to the promoter of DNAJC12 and promoted its transcription and translation. Overexpression of both DNAJC12 and HNF1A promoted cell growth, aerobic glycolysis, and inhibited cell apoptosis in NCI-H1975 and NCI-H1650 cells, as well as the cell apoptosis induced by DDP. In addition, cell growth and aerobic glycolysis mediated DNAJC12 were reversed by the silencing of β-catenin, and downregulation of DNAJC12 abolished the above roles of HNF1A.Conclusions: This study revealed that DNAJC12, activated by the transcription factor HNF1A, could enhance aerobic glycolysis and drug resistance to DDP in NSCLC through regulating β-catenin expression.

show abstract

A novel heat shock protein inhibitor KU757 with efficacy in lenvatinib-resistant follicular thyroid cancer cells overcomes up-regulated glycolysis in drug-resistant cells in vitro

Cited by 10 publications

References 21 publications

Targeting NOX4 disrupts the resistance of papillary thyroid carcinoma to chemotherapeutic drugs and lenvatinib

Targeting NOX4 disrupts the resistance of papillary thyroid carcinoma to chemotherapeutic drugs and lenvatinib

HSP90AB1 Promotes the Proliferation, Migration, and Glycolysis of Head and Neck Squamous Cell Carcinoma

DNAJC12 activated by HNF1A enhances aerobic glycolysis and drug resistance in non-small cell lung cancer

Contact Info

Product

Resources

About