High concentration calcitriol induces endoplasmic reticulum stress related gene profile in breast cancer cells

Ozkaya, Ali Burak; Ak, Handan; Aydin, Hikmet Hakan

doi:10.1139/bcb-2016-0037

Cited by 15 publications

(14 citation statements)

References 44 publications

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“…Recent studies have demonstrated that Nupr1 as a pro-survival gene while CHOP has pro-death functions associated with ER stress induced by calcitriol (Ozkaya et al, 2017). Nupr1 mediates its apoptotic effect through upregulation of the ER stress-related proteins ATF-4, CHOP and Trib3 (Carracedo et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Nupr1 Modulates Methamphetamine-Induced Dopaminergic Neuronal Apoptosis and Autophagy through CHOP-Trib3-Mediated Endoplasmic Reticulum Stress Signaling Pathway

Huang

Tai

et al. 2017

Front. Mol. Neurosci.

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Methamphetamine (METH) is an illegal and widely abused psychoactive stimulant. METH exposure causes detrimental effects on multiple organ systems, primarily the nervous system, especially dopaminergic pathways, in both laboratory animals and humans. In this study, we hypothesized that Nuclear protein 1 (Nupr1/com1/p8) is involved in METH-induced neuronal apoptosis and autophagy through endoplasmic reticulum (ER) stress signaling pathway. To test this hypothesis, we measured the expression levels of Nupr1, ER stress protein markers CHOP and Trib3, apoptosis-related protein markers cleaved-caspase3 and PARP, as well as autophagy-related protein markers LC3 and Beclin-1 in brain tissues of adult male Sprague-Dawley (SD) rats, rat primary cultured neurons and the rat adrenal pheochromocytoma cells (PC12 cells) after METH exposure. We also determined the effects of METH exposure on the expression of these proteins after silencing Nupr1, CHOP, or Trib3 expression with synthetic small hairpin RNA (shRNA) or siRNA in vitro, and after silencing Nupr1 in the striatum of rats by injecting lentivirus containing shRNA sequence targeting Nupr1 gene to rat striatum. The results showed that METH exposure increased Nupr1 expression that was accompanied with increased expression of ER stress protein markers CHOP and Trib3, and also led to apoptosis and autophagy in rat primary neurons and in PC12 cells after 24 h exposure (3.0 mM), and in the prefrontal cortex and striatum of rats after repeated intraperitoneal injections (15 mg/kg × 8 injections at 12 h intervals). Silencing of Nupr1 expression partly reduced METH-induced apoptosis and autophagy in vitro and in vivo. These results suggest that Nupr1 plays an essential role in METH-caused neuronal apoptosis and autophagy at relatively higher doses and may be a potential therapeutic target in high-dose METH-induced neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

Nupr1 Modulates Methamphetamine-Induced Dopaminergic Neuronal Apoptosis and Autophagy through CHOP-Trib3-Mediated Endoplasmic Reticulum Stress Signaling Pathway

Huang

Tai

et al. 2017

Front. Mol. Neurosci.

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“…These factors include key canonical ER stress and UPR genes such as ATF4, DDIT3 (CHOP), PPP1R15A (GADD34), GADD45A (GADD45), XBP1, EIF2AK3 (PERK), and ATF3. Furthermore, IPA of NCI-H1703 cells treated with SSO Ex5 indicated that the top activated upstream pathways consist of gene networks that have been directly or indirectly linked to ER stress and the UPR [NUPR1 (32)(33)(34), z score = 9.34, P = 2.01 × 10 −11 ; MAP4K4 (35,36), z score = 5.04, P = 3.54 × 10 −10 ; ATF4 (37,38), z score = 3.82, P = 4.56 × 10 −10 ; CREB1 (39), z score = 3.06, P = 0.0174; EIF2AK3 (37,38), z score = 3.04, P = 2.54 × 10 − 7 ; CDKN1A (40), z score = 2.99, P = 0.00145] (Fig. 5B).…”

Section: Sso Ex5 Causes Endoplasmic Reticulum Stress and Activates Thementioning

confidence: 99%

Splice switching an oncogenic ratio of SmgGDS isoforms as a strategy to diminish malignancy

Brandt

McNally

Lorimer

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The chaperone protein SmgGDS promotes cell-cycle progression and tumorigenesis in human breast and nonsmall cell lung cancer. Splice variants of SmgGDS, named SmgGDS-607 and SmgGDS-558, facilitate the activation of oncogenic members of the Ras and Rho families of small GTPases through membrane trafficking via regulation of the prenylation pathway. SmgGDS-607 interacts with newly synthesized preprenylated small GTPases, while SmgGDS-558 interacts with prenylated small GTPases. We determined that cancer cells have a high ratio of SmgGDS-607:SmgGDS-558 (607:558 ratio), and this elevated ratio is associated with reduced survival of breast cancer patients. These discoveries suggest that targeting SmgGDS splicing to lower the 607:558 ratio may be an effective strategy to inhibit the malignant phenotype generated by small GTPases. Here we report the development of a splice-switching oligonucleotide, named SSO Ex5, that lowers the 607:558 ratio by altering exon 5 inclusion in SmgGDS pre-mRNA (messenger RNA). Our results indicate that SSO Ex5 suppresses the prenylation of multiple small GTPases in the Ras, Rho, and Rab families and inhibits ERK activity, resulting in endoplasmic reticulum (ER) stress, the unfolded protein response, and ultimately apoptotic cell death in breast and lung cancer cell lines. Furthermore, intraperitoneal (i.p.) delivery of SSO Ex5 in MMTV-PyMT mice redirects SmgGDS splicing in the mammary gland and slows tumorigenesis in this aggressive model of breast cancer. Taken together, our results suggest that the high 607:558 ratio is required for optimal small GTPase prenylation, and validate this innovative approach of targeting SmgGDS splicing to diminish malignancy in breast and lung cancer.

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“…PSMD4 is a well‐known proteasome ubiquitin receptor, and dysfunction in proteasome‐related protein degradation is tightly correlated with ERS . When misfolded proteins accumulate due to a damaged proteasome degradation system, the ERS level exceeds its own repair capability, and cell apoptosis is induced . We then attempted to reveal the possible correlation between PSMD4 and ERS.…”

Section: Discussionmentioning

confidence: 99%

“…32 When misfolded proteins accumulate due to a damaged proteasome degradation system, the ERS level exceeds its own repair capability, and cell apoptosis is induced. 33 We then attempted to reveal the possible correlation between PSMD4 and ERS. Western blot analysis demonstrated that silencing PSMD4 significantly increased the expression of GRP78, ATF6, and p-PERK, indicating an enhanced ERS response in EC cells.…”

Section: Discussionmentioning

confidence: 99%

PSMD4 regulates the malignancy of esophageal cancer cells by suppressing endoplasmic reticulum stress

Zhao

et al. 2019

The Kaohsiung J of Med Scie

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Proteasome 26S subunit non‐ATPase 4 (PSMD4) is an important proteasome ubiquitin receptor and plays a key role in endoplasmic reticulum stress (ERS). However, the study of PSMD4 in esophageal cancer (EC) is relatively rare. Here, we found that the expression of PSMD4 was markedly enhanced in EC tissues and cell lines. The cell counting kit‐8 (CCK‐8) assay showed that overexpression of PSMD4 significantly enhanced Eca109 cell viability, while inhibition of PSMD4 reduced Eca109 cell viability. Knockdown of PSMD4 induced Eca109 cell apoptosis and cell cycle arrest. More importantly, knockdown of PSMD4 significantly enhanced the expression of glucose regulated protein 78, activating transcription factor 6, and p‐protein kinase R‐like ER kinase, indicating an enhanced ERS response in esophageal cancer cells. Compared with the control cells, brefeldin A significantly inhibited the expression of PSMD4 and increased the expression of p53‐upregulated modulator of apoptosis. However, such effects were largely reversed after overexpressing PSMD4 in Eca109 cells, suggesting that silencing PSMD4 could enhance ERS‐induced cell apoptosis. In summary, upregulation of PSMD4 promoted the progression of esophageal cancer mainly by reducing ERS‐induced cell apoptosis.

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High concentration calcitriol induces endoplasmic reticulum stress related gene profile in breast cancer cells

Cited by 15 publications

References 44 publications

Nupr1 Modulates Methamphetamine-Induced Dopaminergic Neuronal Apoptosis and Autophagy through CHOP-Trib3-Mediated Endoplasmic Reticulum Stress Signaling Pathway

Nupr1 Modulates Methamphetamine-Induced Dopaminergic Neuronal Apoptosis and Autophagy through CHOP-Trib3-Mediated Endoplasmic Reticulum Stress Signaling Pathway

Splice switching an oncogenic ratio of SmgGDS isoforms as a strategy to diminish malignancy

PSMD4 regulates the malignancy of esophageal cancer cells by suppressing endoplasmic reticulum stress

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