Improvement of chemotherapeutic drug efficacy by endoplasmic reticulum stress

Mihailidou, Chrysovalantou; Chatzistamou, Ioulia; Papavassiliou, Athanasios G.; Kiaris, Hippokratis

doi:10.1530/erc-15-0019

Cited by 36 publications

(41 citation statements)

References 23 publications

(23 reference statements)

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“…Elucidation of the shift toward the pro-apoptotic function of the UPR promises application in the management of various ER stress-associated conditions such as diabetes and neurodegeneration. Other and our labs recently demonstrated the pivotal role of p21 in this process by mechanisms involving inhibition of p21 expression during the advanced stages of ER stress (23,24,26,28). Consistent with these findings, p21 suppression is permissive for the induction of ER stressrelated apoptosis, as it decreases the apoptotic cut-off of cells undergoing ER stress (27).…”

Section: Introductionsupporting

confidence: 77%

“…To see this illustration in color, the reader is referred to the web version of this article at www.liebert pub.com/ars activation is induced. The fact that p21 ablation was insufficient to abrogate the increased sensitivity of the aged islets to high glucose and tunicamycin (aged p21KO islets remained more sensitive than younger islets), despite that it is regulated by CHOP (23,24), suggests that CHOP attains these aging-associated effects by p21-independent mechanisms. To that end, although CHOP's activity is instructive for ER stress-associated apoptosis, for p21 such activity is rather permissive.…”

Section: Discussionmentioning

confidence: 99%

“…ROS, reactive oxygen species. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars which, considering the inhibitory role of CHOP in p21 expression (23,24) and the previously reported stimulation of ER stress-associated components during aging (30,41), was unexpected. However, relative CHOP induction and occupancy of p21 promoter were more pronounced in the aged islets, which underlines the significance of the inducibility rather than the absolute expression levels during the UPR.…”

Section: Discussionmentioning

confidence: 99%

“…We have recently shown that at least partly, p21 is regulated by CHOP at the level of transcription by a mechanism involving the binding of CHOP to the promoter of p21 (23,24). To test whether differential binding occurs in the promoter of p21 by CHOP, we performed chromatin immunoprecipitation (ChIP) studies in islets from young and aged mice after induction of ER stress by tunicamycin and high glucose.…”

Section: Age-dependent Binding Of Chop At the P21 Promotermentioning

confidence: 99%

“…In the context of diabetes, our laboratory demonstrated that genetic ablation of p21 sensitizes mice to diet-induced diabetes whereas its pharmacological stimulation is protective by improving the survival and function of pancreatic islets (23). Mechanistically, the suppression of p21 during ER stress is produced both directly, by mechanisms involving the transcriptional regulation of p21 by CHOP, and indirectly by engaging an alternative form of the p53 tumor suppressor gene that can inhibit p21 expression (24,28).…”

Section: Introductionmentioning

confidence: 99%

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Modulation of Pancreatic Islets' Function and Survival During Aging Involves the Differential Regulation of Endoplasmic Reticulum Stress by p21 and CHOP

Mihailidou

Chatzistamou

Papavassiliou

et al. 2017

Antioxidants & Redox Signaling

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Aims: Although endoplasmic reticulum (ER) stress is recognized as a major mechanism causing pancreatic dysfunction in diabetes, little is known on how aging modulates the process. Here, we compared the response with ER stress, viability, and insulin release from pancreatic islets of young (6 weeks) or aged (14 months) mice. Results: Islets from aged mice were more sensitive to ER stress than their younger counterparts; they exhibited more pronounced unfolded protein response (UPR) and caspase activation and displayed compromised insulin release after high-glucose stimulation. Genetic ablation of p21 sensitized the islets to ER stress, especially in the aged group, whereas CHOP ablation was protective for islets from both aged and younger animals. Ciclopirox (CPX), an iron chelator that stimulates p21 expression, protected islets from glucotoxicity and mice from dietinduced diabetes, especially in the aged group in a manner that was both p21 and CHOP dependent. Innovation: For the first time, the study shows that age-dependent susceptibility to diet-induced diabetes is associated with the activity of p21 and CHOP in pancreatic islets and that CPX protects islets from glucotoxicity and mice from diabetes in an age-dependent manner. Conclusions: Our results identify ER stress as an age-dependent modifier of islet survival and function by mechanisms implicating enhancement of CHOP activity and inhibition of the protective activity of p21. These findings suggest that interventions restoring the homeostatic activity of ER stress, by agents such as CPX, may be particularly beneficial for the management of diabetes in the elderly. Antioxid. Redox Signal. 27,[185][186][187][188][189][190][191][192][193][194][195][196][197][198][199][200]

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Section: Introductionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Age-dependent Binding Of Chop At the P21 Promotermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Modulation of Pancreatic Islets' Function and Survival During Aging Involves the Differential Regulation of Endoplasmic Reticulum Stress by p21 and CHOP

Mihailidou

Chatzistamou

Papavassiliou

et al. 2017

Antioxidants & Redox Signaling

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The CDK inhibitor p21 is a novel target gene of ATF4 and contributes to cell survival under ER stress

et al. 2017

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Activating transcription factor 4 (ATF4) is well known for its role in the endoplasmic reticulum (ER) stress response. ATF4 also transcriptionally induces multiple effectors that determine cell fate depending on cellular context. In addition, ATF4 can communicate both pro-apoptotic and pro-survival signals. How ATF4 mediates its prosurvival roles, however, requires further investigation. Here, we report that the CDK inhibitor p21 is a novel target gene of ATF4. We identified two ATF4-responsive elements, one of which directly binds ATF4, within the first intron of the p21 gene. Importantly, overexpression of p21 enhances cell survival following ER stress induction, while p21 knockdown increases cell death. These results suggest that p21 induction plays a vital role in the cellular response to ER stress and indicate that p21 is a prosurvival effector of ATF4.

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FAM172A supervises ER (endoplasmic reticulum) stress‐triggered autophagy in the epidural fibrosis process

Zheng

Zhang

et al. 2022

JOR Spine

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Backgrounds: Lumbar laminectomy is usually utilized for lumbar disc herniation (LDH), but also causes epidural fibrosis (EF) process associated with abnormal proliferation of fibroblasts. FAM172A is associated with ER stress and cell proliferation, but its mechanism was unclear, especially in the process of EF.Methods: Therefore, the regulation of FAM172A on the calcium flux and autophagy in fibroblasts were investigated by inducing ER stress with tunicamycin and upexpression or downexpression of FAM172A. The calcium flux was determined using Fluo-3, and autophagy was examined with immunofluorescence or western blot for LC3, Beclin-1, ATG-5, and p62. Moreover, the apoptotic protein of Bax and Bcl-2 was detected, too. Furthermore, the laminectomy model was constructed and then dealt with overexpression of FAM172A.Results: Tunicamycin-induced endoplasmic reticulum (ER) stress and autophagy process in fibroblasts were associated with the calcium flux regulated by FAM172A, especially in EF cells. Besides, tunicamycin induced autophagy and suppressed cell apoptosis of fibroblasts. Furthermore, FAM72A repressed the proliferation of fibroblasts and the process of EF in the laminectomy model through the mediation of the autophagy process.Conclusions: Tunicamycin-induced endoplasmic reticulum (ER) stress in fibroblasts was associated with calcium flux mediated by FAM172A. FAM72A participated in the autophagy regulation of fibroblasts and maybe the key interaction regulator of apoptosis and autophagy in fibroblasts, especially for epidural scar cells.

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Improvement of chemotherapeutic drug efficacy by endoplasmic reticulum stress

Cited by 36 publications

References 23 publications

Modulation of Pancreatic Islets' Function and Survival During Aging Involves the Differential Regulation of Endoplasmic Reticulum Stress by p21 and CHOP

Modulation of Pancreatic Islets' Function and Survival During Aging Involves the Differential Regulation of Endoplasmic Reticulum Stress by p21 and CHOP

The CDK inhibitor p21 is a novel target gene of ATF4 and contributes to cell survival under ER stress

FAM172A supervises ER (endoplasmic reticulum) stress‐triggered autophagy in the epidural fibrosis process

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