HIF‐1α‐regulated stanniocalcin‐1 mediates gemcitabine resistance in pancreatic ductal adenocarcinoma via PI3K/AKT signaling pathway

Zhao, Fangyu; Ye, Gang; Qiu, Jiangdong; Liu, Yueze; Tao, Jinxin; Chen, Guangyu; Su, Dan; You, Lei; Zheng, Lianfang; Zhang, Taiping; Zhao, Yupei

doi:10.1002/mc.23420

Cited by 11 publications

(4 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The elevated expression of STC2 in cervical cancer cells has been reported to significantly increase cisplatin resistance 38 . Both in vivo and in vitro results indicated that STC1 mediated gemcitabine resistance in pancreatic ductal adenocarcinoma 39 . Our previous study showed that sunitinib treatments reduced the expression of STC2 both mRNA and protein levels, which could reduce sunitinib resistance of Caki-1 cells 30 .…”

Section: Discussionmentioning

confidence: 98%

Inhibiting stanniocalcin 2 reduces sunitinib resistance of Caki-1 renal cancer cells under hypoxia condition

Chu,

Xie,

Guo

et al. 2023

Annals of Medicine &Amp; Surgery

View full text Add to dashboard Cite

Background: Our previous study has suggested that blocking stanniocalcin 2 (STC2) could reduce sunitinib resistance in clear cell renal cell carcinoma (ccRCC) under normoxia. The hypoxia is a particularly important environment for RCC occurrence and development, as well as sunitinib resistance. We proposed that STC2 also plays important roles in RCC sunitinib resistance under hypoxia conditions. Methods: The ccRCC Caki-1 cells were treated within the hypoxia conditions. Real-time quantitative PCR and Western blotting were applied to detect the STC2 expression in ccRCC Caki-1 cells. STC2-neutralizing antibodies, STC2 siRNA, and the recombinant human STC2 (rhSTC2) were used to identify targeting regulation on STC2 in modulating sunitinib resistance, proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion. In addition, autophagy flux and the lysosomal acidic environment were investigated by Western blotting and fluorescence staining, and the accumulation of sunitinib in cells was observed with the addition of STC2-neutralizing antibodies and autophagy modulators. Results: Under hypoxia conditions, sunitinib disrupted the lysosomal acidic environment and accumulated in Caki-1 cells. Hypoxia induced the STC2 mRNA and protein levels in Caki-1 cells. STC2-neutralizing antibodies and STC2 siRNA effectively aggravated sunitinib-reduced cell viability and proliferation, which were reversed by rhSTC2. In addition, sunitinib promoted EMT, migration, and invasion, which were reduced by STC2-neutralizing antibodies. Conclusion: Inhibiting STC2 could reduce sunitinib resistance of ccRCC cells under hypoxia conditions.

show abstract

Section: Discussionmentioning

confidence: 98%

Inhibiting stanniocalcin 2 reduces sunitinib resistance of Caki-1 renal cancer cells under hypoxia condition

Chu,

Xie,

Guo

et al. 2023

Annals of Medicine &Amp; Surgery

View full text Add to dashboard Cite

show abstract

“…The GEM resistance-associated gene stanniocalcin-1 (STC1) is related to the prognosis of patients with adjuvant GEM chemotherapy after surgery. Recently, cell and animal models have further validated that STC1 mediates chemoresistance to PC under the action of the HIF-1α/STC1/PI3K-AKT axis ( Zhao et al, 2022 ). Long noncoding RNA antisense RNA1 of HIF1α (lncRNA HIF-1α-AS1) also promotes GEM resistance in PC cells through the AKT/YB1/HIF-1α pathway ( Xu F. et al, 2021 ).…”

Section: Alterations In Glucose Metabolismmentioning

confidence: 99%

The role of metabolic reprogramming in pancreatic cancer chemoresistance

Liu

2023

Front. Pharmacol.

View full text Add to dashboard Cite

Pancreatic cancer is characterized by hidden onset, high malignancy, and early metastasis. Although a few cases meet the surgical indications, chemotherapy remains the primary treatment, and the resulting chemoresistance has become an urgent clinical problem that needs to be solved. In recent years, the importance of metabolic reprogramming as one of the hallmarks of cancers in tumorigenesis has been validated. Metabolic reprogramming involves glucose, lipid, and amino acid metabolism and interacts with oncogenes to affect the expression of key enzymes and signaling pathways, modifying the tumor microenvironment and contributing to the occurrence of drug tolerance. Meanwhile, the mitochondria are hubs of the three major nutrients and energy metabolisms, which are also involved in the development of drug resistance. In this review, we summarized the characteristic changes in metabolism during the progression of pancreatic cancer and their impact on chemoresistance, outlined the role of the mitochondria, and summarized current studies on metabolic inhibitors.

show abstract

“…The PTEN/PI3K/AKT pathway is important in regulating gemcitabine chemosensitivity of pancreatic cancer [36][37][38][39]. Therefore, we aimed to investigate whether FTO and NEDD4 affect gemcitabine chemosensitivity by modulating the PTEN/PI3K/AKT pathway.…”

Section: Nedd4 Regulated By Fto and Ythdf2 Affects The Chemosensitivi...mentioning

confidence: 99%

m6A eraser FTO impairs gemcitabine resistance in pancreatic cancer through influencing NEDD4 mRNA stability by regulating the PTEN/PI3K/AKT pathway

Lin,

Zhou,

Shi

et al. 2023

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background Gemcitabine resistance has brought great challenges to the treatment of pancreatic cancer. The N6-methyladenosine (m6A) mutation has been shown to have a significant regulatory role in chemosensitivity; however, it is not apparent whether gemcitabine resistance can be regulated by fat mass and obesity-associated protein (FTO). Methods Cells with established gemcitabine resistance and tissues from pancreatic cancer patients were used to evaluate FTO expression. The biological mechanisms of the effects of FTO on gemcitabine resistant cells were investigated using CCK-8, colony formation assay, flow cytometry, and inhibitory concentration 50. Immunoprecipitation/mass spectrometry, MeRIP-seq, RNA sequencing and RIP assays, RNA stability, luciferase reporter, and RNA pull down assays were employed to examine the mechanism of FTO affecting gemcitabine resistant pancreatic cancer cells. Results The results revealed that FTO was substantially expressed in cells and tissues that were resistant to gemcitabine. Functionally, the gemcitabine resistance of pancreatic cancer could be enhanced by FTO, while its depletion inhibited the growth of gemcitabine resistant tumor cells in vivo. Immunoprecipitation/mass spectrometry showed that the FTO protein can be bound to USP7 and deubiquitinated by USP7, leading to the upregulation of FTO. At the same time, FTO knockdown significantly decreased the expression level of NEDD4 in an m6A-dependent manner. RNA pull down and RNA immunoprecipitation verified YTHDF2 as the reader of NEDD4, which promoted the chemoresistance of gemcitabine resistant cells. FTO knockdown markedly increased the PTEN expression level in an NEDD4-dependent manner and influenced the chemosensitivity to gemcitabine through the PI3K/AKT pathway in pancreatic cancer cells. Conclusion In conclusion, we found that gemcitabine resistance in pancreatic cancer can be influenced by FTO that demethylates NEDD4 RNA in a m6A-dependent manner, which then influences the PTEN expression level and thereby affects the PI3K/AKT pathway. We also identified that the FTO level can be upregulated by USP7.

show abstract

HIF‐1α‐regulated stanniocalcin‐1 mediates gemcitabine resistance in pancreatic ductal adenocarcinoma via PI3K/AKT signaling pathway

Cited by 11 publications

References 27 publications

Inhibiting stanniocalcin 2 reduces sunitinib resistance of Caki-1 renal cancer cells under hypoxia condition

Inhibiting stanniocalcin 2 reduces sunitinib resistance of Caki-1 renal cancer cells under hypoxia condition

The role of metabolic reprogramming in pancreatic cancer chemoresistance

m6A eraser FTO impairs gemcitabine resistance in pancreatic cancer through influencing NEDD4 mRNA stability by regulating the PTEN/PI3K/AKT pathway

Contact Info

Product

Resources

About