Negative feedback and modern anti‐cancer strategies targeting the ER stress response

Liu, Yaofu; Tan, Zhenzhi; Yang, Yili

doi:10.1002/1873-3468.14000

Cited by 8 publications

(7 citation statements)

References 157 publications

(182 reference statements)

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“…Analysis of TCGA, GEO databases, and human tissue samples demonstrated a robust positive correlation between AURKA and increased UPR/ER stress in EAC. Recent studies indicated that IRE1α, PERK, and ATF6 are essential ER stress sensors, regulating the balance between cell survival and death during ER stress through UPR [33]. Our data not only indicated a remarkable increase in UPR proteins in EAC cells but also showed the critical prosurvival role of IRE1α compared with the other two primary ER stress sensors, PERK and ATF6.…”

Section: Discussionsupporting

confidence: 62%

“…As we showed the co-overexpression of AURKA and UPR key proteins, our data indicated that AURKA induced IRE1α levels and phosphorylation in EAC cells. IRE1α and its downstream sXBP1 promote cell survival during ER stress in several malignancies [33,46].…”

Section: Discussionmentioning

confidence: 99%

“…UPR is known to be activated under ER stress in both normal and cancer cells [31,32]. Since few reports are published on the relationship of AURKA and ER stress, we further looked at our esophageal tissue samples and the TCGA database for BIP mRNA, a marker of ER stress [33] AURKA mRNA expression in EAC. Using RT-PCR in 30 normal esophageal samples and 32 EAC tissues, we detected a significant overexpression of both AURKA and BIP mRNA in EAC samples compared with the normal esophagus (NE) (Figure 1B, p < 0.01).…”

Section: Aurka Overexpression Correlates With Upr Activation In Eacmentioning

confidence: 99%

“…Western blot results demonstrated that AURKA, p-IRE1α (S724) IRE1α, BIP, XBP1s, p-PERK (T982) PERK, and p-eIF2α(S51) protein expression levels were remarkably higher in Barrett's esophagus and EAC cells compared with normal esophageal tissues (Figure 2A). IRE1α, PERK, and ATF6 are three well-known sensors that activate UPR, controlling the balance between cell survival and apoptosis during ER stress in cancer [33,34]. To test which sensors are vital in EAC cell models, we knocked down these proteins respectively in EAC cell lines using siRNA.…”

Section: Ire1α Promotes Eac Cell Survival Through Aurkamentioning

confidence: 99%

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Unfolded Protein Response Is Activated by Aurora Kinase A in Esophageal Adenocarcinoma

Gomaa

Wang-Bishop

et al. 2022

Cancers

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Unfolded protein response (UPR) protects malignant cells from endoplasmic reticulum stress-induced apoptosis. We report that Aurora kinase A (AURKA) promotes cancer cell survival by activating UPR in esophageal adenocarcinoma (EAC). A strong positive correlation between AURKA and binding immunoglobulin protein (BIP) mRNA expression levels was found in EACs. The in vitro assays indicated that AURKA promoted IRE1α protein phosphorylation, activating prosurvival UPR in FLO-1 and OE33 cells. The use of acidic bile salts to mimic reflux conditions in patients induced high AURKA and IRE1α levels. This induction was abrogated by AURKA knockdown in EAC cells. AURKA and p-IRE1α protein colocalization was observed in neoplastic gastroesophageal lesions of the L2-IL1b mouse model of Barrett’s esophageal neoplasia. The combined treatment using AURKA inhibitor and tunicamycin synergistically induced cancer cell death. The use of alisertib for AURKA inhibition in the EAC xenograft model led to a decrease in IRE1α phosphorylation with a significant reduction in tumor growth. These results indicate that AURKA activates UPR, promoting cancer cell survival during ER stress in EAC. Targeting AURKA can significantly reverse prosurvival UPR signaling mechanisms and decrease cancer cell survival, providing a promising approach for the treatment of EAC patients.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Aurka Overexpression Correlates With Upr Activation In Eacmentioning

confidence: 99%

Section: Ire1α Promotes Eac Cell Survival Through Aurkamentioning

confidence: 99%

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Unfolded Protein Response Is Activated by Aurora Kinase A in Esophageal Adenocarcinoma

Gomaa

Wang-Bishop

et al. 2022

Cancers

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“…However, the triad stress responses of nucleus, ER, and mitochondria also induce oxidative damage, DNA mutations, angiogenesis, and metabolic changes, if sustained in chronic inflammation, conducive to cell malignant transformation and cancer growth (9)(10)(11). The inhibition of ER stress by chemical compounds has demonstrated effective in the preclinical and clinical trials of multiple tumors (12,13).…”

Section: Introductionmentioning

confidence: 99%

PDIA2 Bridges Endoplasmic Reticulum Stress and Metabolic Reprogramming During Malignant Transformation of Chronic Colitis

Tao

et al. 2022

Front. Oncol.

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BackgroundChronic inflammation contributes to approximately 20% of cancers; the underlying mechanisms are still elusive. Here, using an animal model of colitis to colon-cancerous transformation, we demonstrated that endoplasmic reticulum (ER) stress couples with metabolic reprogramming to promote a malignant transformation of chronic inflammation.MethodsThe animal model for chronic colitis to colon-cancerous transformation was established in C57BL/6N mice by azoxymethane (AOM) and dextran sodium sulfate (DSS) treatments. The differential proteins in control and AOM/DSS-treated colon mucosa were determined using proteomic analysis; the kinetics of metabolic modifications were monitored by mitochondrial oxygen flux, extracellular acidification, and targeted metabolomics; the molecule linker between ER stress and metabolic modifications were identified by coimmunoprecipitation, KEGG pathway analysis, and the subcutaneous tumor model using gene-specific knockdown colon cancer cells. Tissue array analysis were used to evaluate the differential protein in cancer and cancer-adjacent tissues.ResultsAOM/DSS treatment induced 38 tumors in 10 mice at the 14th week with the mean tumor size 9.35 ± 3.87 mm2, which was significantly decreased to 5.85 ± 0.95 mm2 by the ER stress inhibitor 4-phenylbutyric acid (4PBA). Seven differential proteins were determined from control (1,067 ± 48) and AOM/DSS-treated mucosa (1,077 ± 59); the level of ER protein PDIA2 (protein disulfide isomerase-associated 2) was increased over 7-fold in response to AOM/DSS treatment. PDIA2 interacted with 420 proteins that were involved in 8 signaling pathways, in particular with 53 proteins in metabolic pathways. PDIA2 translocated from ER to mitochondria and interacted with the components of complexes I and II to inhibit oxophosphorylation but increase glycolysis. Knockdown PDIA2 in colon cancer cells restored the metabolic imbalance and significantly repressed tumor growth in the xenograft animal model. 4PBA therapy inhibited the AOM/DSS-mediated overexpression of PDIA2 and metabolic modifications and suppressed colon cancer growth. In clinic, PDIA2 was overexpressed in colon cancer tissues rather than cancer-adjacent tissues and was related with the late stages and lymph node metastasis of colon cancer.ConclusionsPersistent ER stress reprograms the metabolism to promote the malignant transformation of chronic colitis; PDIA2 serves as a molecule linker between ER stress and metabolic reprogramming. The inhibition of ER stress restores metabolic homeostasis and attenuates the cancerous transformation of chronic inflammation.

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Trim21 modulates endoplasmic reticulum-associated degradation and sensitizes cancer cells to ER stress-induced apoptosis by inhibiting VCP/Npl4/UFD1 assembly

Yuan,

Liao,

et al. 2025

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Negative feedback and modern anti‐cancer strategies targeting the ER stress response

Cited by 8 publications

References 157 publications

Unfolded Protein Response Is Activated by Aurora Kinase A in Esophageal Adenocarcinoma

Unfolded Protein Response Is Activated by Aurora Kinase A in Esophageal Adenocarcinoma

PDIA2 Bridges Endoplasmic Reticulum Stress and Metabolic Reprogramming During Malignant Transformation of Chronic Colitis

Trim21 modulates endoplasmic reticulum-associated degradation and sensitizes cancer cells to ER stress-induced apoptosis by inhibiting VCP/Npl4/UFD1 assembly

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