Unfolded Protein Response (UPR) in Survival, Dormancy, Immunosuppression, Metastasis, and Treatments of Cancer Cells

Hsu, Sheng‐Kai; Chiu, Chien‐Chih; Dahms‬, Hans-Uwe; Chou, Chia-Man; Cheng, C. C.; Chang, Wen Tsan; Cheng, Kai‐Chun; Wang, Hui‐Min David; Lin, I‐Ling

doi:10.3390/ijms20102518

Cited by 89 publications

(75 citation statements)

References 121 publications

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“…Our results showed that the Annexin/PI phenotype was also coupled with the over-expression of many apoptotic proteins when (a) GSK2606414-treated cells were compared with non-treated cells, as well as when (b) GSK2606414/BTZ-treated cells were compared to BTZ-treated cells. Given the dual function of PERK both in cell survival and apoptosis [ 15 , 45 ], we sought to determine whether GGSK2606414 on its own or, more interestingly, in combination with BTZ, would drive cells to increased apoptosis and hence sensitize cells to more effective combination therapies. Among the apoptotic proteins upregulated, survivin has been previously described as being associated with ER stress and UPR gene expression in colonic epithelial cells [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Characterization of a PERK Kinase Inhibitor with Anti-Myeloma Activity

Bagratuni

Patseas

Mavrianou-Koutsoukou

et al. 2020

Cancers

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Due to increased immunoglobulin production and uncontrolled proliferation, multiple myeloma (MM) plasma cells develop a phenotype of deregulated unfolded protein response (UPR). The eIF2-alpha kinase 3 [EIF2αK3, protein kinase R (PKR)-like ER kinase (PERK)], the third known sensor of endoplasmic reticulum (ER) stress, is a serine-threonine kinase and, like the other two UPR-related proteins, i.e., IRE1 and ATF6, it is bound to the ER membrane. MM, like other tumors showing uncontrolled protein secretion, is highly dependent to UPR for survival; thus, inhibition of PERK can be an effective strategy to suppress growth of malignant plasma cells. Here, we have used GSK2606414, an ATP-competitive potent PERK inhibitor, and found significant anti-proliferative and apoptotic effects in a panel of MM cell lines. These effects were accompanied by the downregulation of key components of the PERK pathway as well as of other UPR elements. Consistently, PERK gene expression silencing significantly increased cell death in MM cells, highlighting the importance of PERK signaling in MM biology. Moreover, GSK2606414, in combination with the proteasome inhibitor bortezomib, exerted an additive toxic effect in MM cells. Overall, our data suggest that PERK inhibition could represent a novel combinatorial therapeutic approach in MM.

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Section: Discussionmentioning

confidence: 99%

Characterization of a PERK Kinase Inhibitor with Anti-Myeloma Activity

Bagratuni

Patseas

Mavrianou-Koutsoukou

et al. 2020

Cancers

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“…A robust UPR induction, causes lethal ER stress. 38 However, a moderate induction of that pathway has been associated with protective responses in the endothelium. 39 In particular, the transfection of human pulmonary artery endothelial cells with siRNA for BiP (the ER Hsp70) promoted the filamentous actin formation and abrogated endothelial permeability.…”

Section: Discussionmentioning

confidence: 99%

GHRH antagonists support lung endothelial barrier function

et al. 2019

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Growth Hormone-Releasing Hormone (GHRH) regulates the release of growth hormone from the anterior pituitary gland. GHRH also acts as a growth and inflammatory factor in a variety of experimental models in oncology. In the current study, we used bovine pulmonary arterial cells in order to investigate the effects of GHRH and its antagonistic and agonistic analogs in key intracellular pathways that regulate endothelial permeability. GHRH antagonists suppressed the activation of MLC2, ERK1/2, JAK2/STAT3 pathway and increased the intracellular P53 and pAMPK levels. In contrast, both GHRH and GHRH agonist MR409 exerted the opposite effects. Furthermore, GHRH antagonists supported the integrity of endothelial barrier, while GHRH and GHRH agonists had the contrary effects, as reflected in measurements of transendothelial resistance. Our observations support the evidence for the antiinflammatory role of GHRH antagonists in the vasculature. Moreover, our results suggest that GHRH antagonists should be considered as promising therapeutic agents for treating severe respiratory abnormalities, such as the lethal Acute Respiratory Distress Syndrome (ARDS).

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“…Due to the addition of a phenyl group, PBA acquires also the capacity to act as chemical chaperone and may consequently help to restore the proper conformation of unfolded proteins, whose accumulation induces ER stress. ER stress/Unfolded Protein Response (UPR), usually activated in the cancer cells due to the intrinsic or extrinsic insults, may sustain cancer survival/chemoresistance [1]. Both PBA and NaB are histone deacetylase inhibitors (HDACis), and as such, they may hold a strong anti-cancer potential [2], also at sublethal doses.…”

Section: Introductionmentioning

confidence: 99%

PBA Preferentially Impairs Cell Survival of Glioblastomas Carrying mutp53 by Reducing Its Expression Level, Stabilizing wtp53, Downregulating the Mevalonate Kinase and Dysregulating UPR

et al. 2020

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Phenylbutyrate (PBA) is a derivative of Butyric Acid (BA), which has the characteristics of being a histone deacetylase (HDAC) inhibitor and acting as a chemical chaperone. It has the potential to counteract a variety of different diseases, from neurodegeneration to cancer. In this study, we investigated the cytotoxic effect of PBA against glioblastoma cells carrying wt or mutant (mut) p53 and found that it exerted a higher cytotoxic effect against the latter in comparison with the former. This could be due to the downregulation of mutp53, to whose pro-survival effects cancer cells become addicted. In correlation with mutp53 reduction and wtp53 activation, PBA downregulated the expression level of mevalonate kinase (MVK), a key kinase of the mevalonate pathway strongly involved in cancer cell survival. Here we differentiated the chaperoning function of PBA from the others anti-cancer potentiality by comparing its effects to those exerted by NaB, another HDACi that derives from BA but, lacking the phenyl group, cannot act as a chemical chaperone. Interestingly, we observed that PBA induced a stronger cytotoxic effect compared to NaB against U373 cells as it skewed the Unfolded Protein Response (UPR) towards cell death induction, upregulating CHOP and downregulating BIP, and was more efficient in downregulating MVK. The findings of this study suggest that PBA represents a promising molecule against glioblastomas, especially those carrying mutp53, and its use, approved by FDA for urea cycle disorders, should be extended to the glioblastoma anticancer therapy.

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Unfolded Protein Response (UPR) in Survival, Dormancy, Immunosuppression, Metastasis, and Treatments of Cancer Cells

Cited by 89 publications

References 121 publications

Characterization of a PERK Kinase Inhibitor with Anti-Myeloma Activity

Characterization of a PERK Kinase Inhibitor with Anti-Myeloma Activity

GHRH antagonists support lung endothelial barrier function

PBA Preferentially Impairs Cell Survival of Glioblastomas Carrying mutp53 by Reducing Its Expression Level, Stabilizing wtp53, Downregulating the Mevalonate Kinase and Dysregulating UPR

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