CCT4 knockdown enhances the sensitivity of cisplatin by inhibiting glycolysis in human esophageal squamous cell carcinomas

Fang, Jiarui; Ma, Yingchao; Li, Ya; Li, Jianhui; Zhang, Xishen; Han, Xiao Yu; Ma, Shanshan; Guan, Fangxia

doi:10.1002/mc.23460

Cited by 10 publications

(12 citation statements)

References 46 publications

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“…To further analyse the role of dysregulated RTKs on chemoresistance under simulated conditions of limited oxygen (1%), we initially considered the selection of OSCC cell lines that had the greatest resistance to DDP. Recent findings have indicated that KYSE150 cells have the lowest drug sensitivity to DDP [ 21 ]. We thus examined the IC 50 of DDP in different cell lines under low-oxygen conditions and found that this was indeed the case (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia

Fang

Sun

Leng

et al. 2023

J Exp Clin Cancer Res

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Background Cisplatin (DDP)-based chemotherapy is commonly adopted as the first-line treatment for patients with oesophageal squamous cell carcinoma (OSCC), but the high rate of drug resistance limits its clinical application and the underlying mechanisms at play remain unclear. The aims of this study were to elucidate the role of abnormal signal transmission and metabolism in the chemoresistance of OSCC under hypoxia and to identify targeted drugs that enhance the sensitivity of DDP chemotherapy. Methods Upregulated genes in OSCC were determined by RNA sequencing (RNA-seq), the Cancer Genome Atlas (TCGA) database, immunohistochemistry (IHC), real-time quantitative PCR (RT-qPCR), and western blotting (WB). The clinicopathological significance of insulin-like growth factor-I receptor (IGF1R), argininosuccinate synthetase 1 (ASS1), and pyrroline-5-carboxylate reductase 1 (PYCR1) in OSCC was analysed using tissue micriarray (TMA). Metabolic abnormalities were determined by untargeted metabolomics analysis. The DDP-resistance role of IGF1R, ASS1, and PYCR1 in OSCC was investigated in vitro and in vivo. Results Generally, tumour cells exist in a hypoxic microenvironment. By genomic profiling, we determined that IGF1R, as a receptor tyrosine kinase (RTK), was upregulated in OSCC under low-oxygen conditions. Clinically, enhanced IGF1R expression was associated with higher tumour stages and a poorer prognosis in OSCC patients, and its inhibitor, linsitinib, showed synergistic effects with DDP therapy in vivo and in vitro. Since oxygen-deprivation frequently lead to metabolic reprogramming, we further learned via metabolomics analysis that abnormal IGF1R pathways promoted the expression of metabolic enzymes ASS1 and PYCR1 by the transcriptional activity of c-MYC. In detail, enhanced expression of ASS1 promotes arginine metabolism for biological anabolism, whereas PYCR1 activates proline metabolism for redox balance, which maintains the proliferation ability of OSCC cells during DDP treatment under hypoxic conditions. Conclusion Enhanced expression of ASS1 and PYCR1 via IGF1R pathways rewired arginine and proline metabolism, promoting DDP resistance in OSCC under hypoxia. Linsitinib targeting IGF1R signaling may lead to promising combination therapy options for OSCC patients with DDP resistance.

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Section: Resultsmentioning

confidence: 99%

Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia

Fang

Sun

Leng

et al. 2023

J Exp Clin Cancer Res

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“…When tumor volume reached about 100 mm 3 , the mice were randomly divided into four groups: CON group, DCA group, DDP group, and DCA + DDP group (5 mice/group). Tumor volume was measured every 3 days, and tumor growth curve was calculated using the formula “length×width 2 × 3.14/6.” The mice were euthanized when the experiment was terminated, and the tumors were collected for further investigation 27 …”

Section: Methodsmentioning

confidence: 99%

“…The mice were euthanized when the experiment was terminated, and the tumors were collected for further investigation. 27…”

Section: In Vivo Tumor Inoculation Mouse Modelmentioning

confidence: 99%

PDK1 regulates the progression of esophageal squamous cell carcinoma through metabolic reprogramming

Zhang

Han

et al. 2023

Molecular Carcinogenesis

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Esophageal squamous cell carcinoma (ESCC) is one of the deadliest human malignancies characterized by late-stage diagnosis, drug resistance, and poor prognosis. Pyruvate dehydrogenase kinase 1 (PDK1) plays an important role in regulating the metabolic reprogramming of cancer cells. However, its expression, function, and regulatory mechanisms of PDK1 in ESCC have not been reported. In this study, we found that PDK1 silence and dichloroacetic acid (DCA) significantly inhibited the growth of ESCC cells and induced cell apoptosis. Interestingly, PDK1 is a direct target of miR-6516-5p, and miR-6516-5p/PDK1 axis suppressed the growth of ESCC cell by inhibiting glycolysis. Moreover, DCA and cisplatin (cis-diamminedichloroplatinum, DDP) synergistically inhibited the progression and glycolysis ability of ESCC cells both in vitro and in vivo by increasing oxidative stress via the inhibition of the Keap1/Nrf2 signaling pathway. And, Tert-butylhydroquinone (TBHQ), a specific activator of the Keap1/Nrf2 signaling, could diminish the synergic antitumor effects of DCA and DDP on ESCC cells. Collectively, our findings indicate that PDK1 may regulate the progression of ESCC by metabolic reprogramming, which provides new strategy for the treatment of ESCC.

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“…75,111,112 Finally, they modulate signalling pathways to promote tumour occurrence and development. 82,113,114 Here, we describe these functions as they relate to the hallmarks of cancer.…”

Section: Cct Subunits In Cancersmentioning

confidence: 99%

“…Second, they regulate the assembly and disassembly of TRiC/CCT and influence its protein folding activity 75,111,112 . Finally, they modulate signalling pathways to promote tumour occurrence and development 82,113,114 . Here, we describe these functions as they relate to the hallmarks of cancer.…”

Section: Cct Subunits In Cancersmentioning

confidence: 99%

Revisiting the chaperonin T‐complex protein‐1 ring complex in human health and disease: A proteostasis modulator and beyond

Zeng,

Han,

Pan

et al. 2024

Clinical & Translational Med

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BackgroundDisrupted protein homeostasis (proteostasis) has been demonstrated to facilitate the progression of various diseases. The cytosolic T‐complex protein‐1 ring complex (TRiC/CCT) was discovered to be a critical player in orchestrating proteostasis by folding eukaryotic proteins, guiding intracellular localisation and suppressing protein aggregation. Intensive investigations of TRiC/CCT in different fields have improved the understanding of its role and molecular mechanism in multiple physiological and pathological processes.Main bodyIn this review, we embark on a journey through the dynamic protein folding cycle of TRiC/CCT, unraveling the intricate mechanisms of its substrate selection, recognition, and intriguing folding and assembly processes. In addition to discussing the critical role of TRiC/CCT in maintaining proteostasis, we detail its involvement in cell cycle regulation, apoptosis, autophagy, metabolic control, adaptive immunity and signal transduction processes. Furthermore, we meticulously catalogue a compendium of TRiC‐associated diseases, such as neuropathies, cardiovascular diseases and various malignancies. Specifically, we report the roles and molecular mechanisms of TRiC/CCT in regulating cancer formation and progression. Finally, we discuss unresolved issues in TRiC/CCT research, highlighting the efforts required for translation to clinical applications, such as diagnosis and treatment.ConclusionThis review aims to provide a comprehensive view of TRiC/CCT for researchers to inspire further investigations and explorations of potential translational possibilities.

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CCT4 knockdown enhances the sensitivity of cisplatin by inhibiting glycolysis in human esophageal squamous cell carcinomas

Cited by 10 publications

References 46 publications

Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia

Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia

PDK1 regulates the progression of esophageal squamous cell carcinoma through metabolic reprogramming

Revisiting the chaperonin T‐complex protein‐1 ring complex in human health and disease: A proteostasis modulator and beyond

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