Active mixture of serum-circulating small molecules selectively inhibits proliferation and triggers apoptosis in cancer cells via induction of ER stress

Scheffer, Dalma; Kulcsár, Gyula; Nagyéri, György; Kiss-Merki, Marianna; Rékási, Zoltán; Maloy, Magnus; Czömpöly, Tamás

doi:10.1016/j.cellsig.2019.109426

Cited by 12 publications

(7 citation statements)

References 59 publications

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“…20 It has been proved that the depletion of GSH is associated with the ROS accumulation and ferroptosis activation. 8,9 CHAC1 is a newly discovered endoplasmic reticulum inducible gene, 21 involved in the γ-glutamyl cycle that can degrade glutathione 22,23 and promote cell apoptosis or ferroptosis. 24,25 Previous research has also demonstrated that CHAC1 is differentially expressed in KIRC.…”

Section: Discussionmentioning

confidence: 99%

Ferroptosis‐related gene CHAC1 is a valid indicator for the poor prognosis of kidney renal clear cell carcinoma

Deng

Liu

et al. 2021

J Cellular Molecular Medi

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To evaluate the validity of CHAC1 for predicting the prognosis of kidney renal clear cell carcinoma (KIRC) and to explore its therapeutic potential for KIRC, we conducted several bioinformatic analyses using the sequencing data and clinical information derived from online databases. We found CHAC1 is down‐regulated in KIRC samples when compared with normal samples but up‐regulated in KIRC samples with relatively higher malignancy and later stages. Univariate cox analysis and multivariate cox regression analysis were conducted and the results revealed up‐regulated CHAC1 is an independent risk factor for poor prognosis of KIRC. Further, the nomogram model based on the result of multivariate cox regression analysis was constructed and effectively predicted patients' 1‐year, 3‐year and 5‐year survival respectively. The correlation analyses showed CHAC1 is associated with the immune pathway markers of memory B cell, natural killer cell and type1 T helper cell as well as the checkpoint genes like ADORA2A, CD200, CD44, CD70, HHLA2, NRP1, PDCD1LG2 and TNFRSF18. Furthermore, experiments in vitro indicated CHAC1 could induce cell death in KIRC cell lines but had limited influence on cell migration and cell invasion. In conclusion, CHAC1 is found a valid indicator for poor prognosis of kidney renal clear cell carcinoma.

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Section: Discussionmentioning

confidence: 99%

Ferroptosis‐related gene CHAC1 is a valid indicator for the poor prognosis of kidney renal clear cell carcinoma

Deng

Liu

et al. 2021

J Cellular Molecular Medi

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“…The top 25 upregulated and downregulated genes are listed in Supplementary Tables S2 and S3, respectively. FAM129A and GDF15 are the top upregulated genes induced by YUM70 that are known to respond to ER stress (27,28). YUM70 treatment induces the transcription of both TRIB3 and SLC1A4 by 13.9 and 13.7 fold respectively (Supplementary Table S2).…”

Section: Yum70 Induces Er Stress-mediated Apoptosismentioning

confidence: 99%

The Hydroxyquinoline Analogue YUM70 Inhibits GRP78 to Induce ER Stress–Mediated Apoptosis in Pancreatic Cancer

et al. 2021

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GRP78 (Glucose-regulated protein, 78 kDa) is a key regulator of ER (endoplasmic reticulum) stress signaling. Cancer cells are highly proliferative and have high demand for protein synthesis and folding, which results in significant stress on the ER. To respond to ER stress and maintain cellular homeostasis, cells activate the unfolded protein response (UPR) that promotes either survival or apoptotic death. Cancer cells utilize the UPR to promote survival and growth. In this study, we describe the discovery of a series of novel hydroxyquinoline GRP78 inhibitors. A representative analog, YUM70, inhibited pancreatic cancer cell growth in vitro and showed in vivo efficacy in a pancreatic cancer xenograft model with no toxicity to normal tissues. YUM70 directly bound GRP78 and inactivated its function, resulting in ER stress-mediated apoptosis. A YUM70 analog conjugated with BODIPY show co-localization of the compound with GRP78 in the ER. Moreover, a YUM70-PROTAC (PROteolysis TArgeting Chimera) was synthesized to force degradation of GRP78 in pancreatic cancer cells. YUM70 showed a strong synergistic cytotoxicity with topotecan and vorinostat. Together, our study demonstrates that YUM70 is a novel inducer of ER stress with preclinical efficacy as a monotherapy or in combination with topoisomerase and HDAC inhibitors in pancreatic cancer. SIGNIFICANCEThis study identifies a novel ER stress inducer that binds GRP78 and inhibits pancreatic cancer cell growth in vitro and in vivo, demonstrating its potential as a therapeutic agent for pancreatic cancer.Research.

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“…The state of cell health during ER stress ultimately decides cell fate (16). Previous studies have demonstrated that an increase in CHAC1 levels was associated with the activation of ER stress (17,18). In the present study, overexpression of CHAC1 significantly upregulated the expression of ER stress-related factors, BIP and CHOP, while co-treatment with GSH inhibited ER stress.…”

Section: Discussionmentioning

confidence: 99%

ChaC glutathione specific γ‑glutamylcyclotransferase 1 inhibits cell viability and increases the sensitivity of prostate cancer cells to docetaxel by inducing endoplasmic reticulum stress and ferroptosis

Zhang

et al. 2021

Exp Ther Med

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The present study aimed to determine the effects and mechanism of ChaC glutathione specific γ-glutamylcyclotransferase 1 (CHAC1) on cell viability and the sensitivity of prostate cancer cells to docetaxel. Compared with non-tumor human prostate epithelial RWPE-1 cells, the mRNA and protein levels of CHAC1 significantly decreased in two prostate cancer cell lines, DU145 and 22RV1, as measured by quantitative polymerase chain reaction and western blot analysis (P<0.05). The cell viability and glutathione (GSH) levels were significantly inhibited in prostate cancer cells following overexpression of CHAC1 (P<0.01), while they were significantly increased in DU145 cells transfected with CHAC1 siRNA (P<0.05), but not in 22RV1 cells (P>0.05). The expression levels of several endoplasmic reticulum (ER) stress-related factors were then measured by western blot analysis. Following transfection with plasmid overexpressing CHAC1, ER markers, BIP and CHOP levels, were significantly upregulated (P<0.01), while GSH co-treatment decreased this upregulation. In addition, CHAC1 protein levels were significantly upregulated in cells treated with a ferroptosis activator (P<0.05). A liperflo reagent was then used to determine intracellular lipid peroxide levels. The intracellular lipid peroxides levels were significantly increased following CHAC1-overexpression (P<0.05), while GPX4 protein levels were significantly decreased (P<0.01). The cell viability was significantly inhibited (P<0.001) even with 1 nM docetaxel (DTX) and a plasmid overexpressing CHAC1, while the effect of inhibition was not significant at 1 nM of DTX alone (P>0.05). This inhibition was also eliminated following the addition of a ferroptosis inhibitor. In summary, CHAC1 may inhibit cell viability and increase the sensitivity of prostate cancer cells to DTX. The cellular mechanism may involve the induction of ER stress and ferroptosis. The results of the present study identified a potentially novel therapeutic target for prostate cancer, which may be useful in patients with castration-resistant prostate cancer.

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Active mixture of serum-circulating small molecules selectively inhibits proliferation and triggers apoptosis in cancer cells via induction of ER stress

Cited by 12 publications

References 59 publications

Ferroptosis‐related gene CHAC1 is a valid indicator for the poor prognosis of kidney renal clear cell carcinoma

Ferroptosis‐related gene CHAC1 is a valid indicator for the poor prognosis of kidney renal clear cell carcinoma

The Hydroxyquinoline Analogue YUM70 Inhibits GRP78 to Induce ER Stress–Mediated Apoptosis in Pancreatic Cancer

ChaC glutathione specific γ‑glutamylcyclotransferase 1 inhibits cell viability and increases the sensitivity of prostate cancer cells to docetaxel by inducing endoplasmic reticulum stress and ferroptosis

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