Reticulocalbin-1 knockdown increases the sensitivity of cells to Adriamycin in nasopharyngeal carcinoma and promotes endoplasmic reticulum stress-induced cell apoptosis

Huang, Zehao; Qiao, Jun; Feng, Ying; Qiu, Mengting; Cheng, Ting; Wang, Jia; Zheng, Chunhua; Lv, Zhiqin; Wang, Caihong

doi:10.1080/15384101.2020.1733750

Cited by 23 publications

(21 citation statements)

References 31 publications

(35 reference statements)

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“…Our current data where knockdown of RCN1 led to enhanced ATF6 activity and over-expression of RCN1 mediated reduced ATF6 activity in cells when challenged with ER stress inducers is consistent with other reports. Similar to our findings, Huang et al, showed that knockdown of RCN1 enhanced the expression of ER stress markers GRP78, CHOP, Herp, Erdj4, ATF4 and EDEM1 and promoted apoptosis in nasopharyngeal carcinoma cells when challenged with the chemotherapeutic adriamycin [ 40 ]. Our current data also showed that RCN1 knockdown leads to enhanced phosphorylation of EIF2α, increased expression of ATF4 and enhanced activity of NRF2, members of another UPR pathway PERK-EIF2α-ATF4 that is divergent to the ATF6 pathway.…”

Section: Discussionsupporting

confidence: 91%

“…Previous findings have demonstrated that the expression of the ER-localized, calcium binding protein RCN1 correlates with progression of breast, liver, kidney, lung, prostate and colorectal cancer [ 19 , 20 , 21 , 37 , 38 , 39 ] and may play an important role in mediating resistance to treatment in uterine and nasopharyngeal carcinoma [ 40 ]. However, it is unclear as to which receptor tyrosine kinases regulate RCN1 expression and whether RCN1 plays a role in glioblastoma progression.…”

Section: Discussionmentioning

confidence: 99%

“…Several reports indicating that RCN1 is responsible for promoting tumor survival in prostate, liver, kidney and skin cancer cell lines under ER stress [ 5 , 38 ]. In addition, RCN1 depletion induced ER stress in animal models and led to cell death [ 38 , 40 ]. However, no study to date has evaluated whether EGFRvIII and RCN1 co-operate to promote glioblastoma survival.…”

Section: Discussionmentioning

confidence: 99%

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EGFRvIII Promotes Cell Survival during Endoplasmic Reticulum Stress through a Reticulocalbin 1-Dependent Mechanism

Gomez

Areeb

Stuart

et al. 2021

Cancers

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Reticulocalbin 1 (RCN1) is an endoplasmic reticulum (ER)-residing protein, involved in promoting cell survival during pathophysiological conditions that lead to ER stress. However, the key upstream receptor tyrosine kinase that regulates RCN1 expression and its potential role in cell survival in the glioblastoma setting have not been determined. Here, we demonstrate that RCN1 expression significantly correlates with poor glioblastoma patient survival. We also demonstrate that glioblastoma cells with expression of EGFRvIII receptor also have high RCN1 expression. Over-expression of wildtype EGFR also correlated with high RCN1 expression, suggesting that EGFR and EGFRvIII regulate RCN1 expression. Importantly, cells that expressed EGFRvIII and subsequently showed high RCN1 expression displayed greater cell viability under ER stress compared to EGFRvIII negative glioblastoma cells. Consistently, we also demonstrated that RCN1 knockdown reduced cell viability and exogenous introduction of RCN1 enhanced cell viability following induction of ER stress. Mechanistically, we demonstrate that the EGFRvIII-RCN1-driven increase in cell survival is due to the inactivation of the ER stress markers ATF4 and ATF6, maintained expression of the anti-apoptotic protein Bcl-2 and reduced activity of caspase 3/7. Our current findings identify that EGFRvIII regulates RCN1 expression and that this novel association promotes cell survival in glioblastoma cells during ER stress.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

EGFRvIII Promotes Cell Survival during Endoplasmic Reticulum Stress through a Reticulocalbin 1-Dependent Mechanism

Gomez

Areeb

Stuart

et al. 2021

Cancers

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“…RCN1 overexpression has been identified in various tumors, including liver, lung, breast, colorectal, prostate, and nasopharyngeal cancers [14][15][16][17][18][19][20]. In particular, RCN1 was implicated in the regulation of drug resistance, and RCN1 knockdown was found to reduce the resistance of nasopharyngeal carcinoma (NPC) cells/ tissues to doxorubicin, promoting NPC cell death [21]. RCN1 was also found to be upregulated in doxorubicin-resistant uterine cancer [22].…”

Section: Introductionmentioning

confidence: 99%

RCN1 induces sorafenib resistance and malignancy in hepatocellular carcinoma by activating c-MYC signaling via the IRE1α–XBP1s pathway

Wang

Liu

et al. 2021

Cell Death Discov.

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The increasing incidence of hepatocellular carcinoma (HCC) is of great concern globally, but the molecular pathogenesis of these tumors remains unclear. Sorafenib is a first-line drug for the treatment of advanced HCC. However, the efficacy of sorafenib in improving patient survival is limited, and most patients inevitably develop resistance to this drug. Recent studies have demonstrated that the activation of the IRE1α–XBP1s pathway might play a protective role in the response to sorafenib and contribute to malignancy in HCC. Here, we found that RCN1, an endoplasmic reticulum resident protein, is significantly upregulated in sorafenib-resistant HCC cells and promotes tumor progression. Our analysis showed that RCN1 may be an independent predictor of tumor recurrence and overall survival. Mechanistically, RCN1 promotes the dissociation of GRP78 from IRE1α in sorafenib-resistant cells by interacting with GRP78 through its EFh1/2 domain. Subsequently, the IRE1α–XBP1s pathway, a branch of the unfolded protein response, is sustainably activated. Interestingly, IRE1α–XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in HCC. These results suggest that RCN1-targeted therapy might be a feasible strategy for the treatment of HCC.

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“…Besides, it was revealed that the ER stress-related genes-based risk model can serve as a prognostic factor to predict the outcome for patients and be correlated with immune and inflammation responses in glioma ( Zhang et al, 2021 ). Among these genes, RCN1, as an ER-resident calcium-binding protein, is verified as one of ER stress-related genes, of which the depletion causes the ER stress-induced cells’ apoptosis in various cancers ( Huang et al, 2020 ; Liu et al, 2018 ; Xu et al, 2017 ). In the early study, it was demonstrated that RCN1 was identified as a genuine phagocytosis ligand to stimulate microglial phagocytosis of apoptotic neurons that were subsequently targeted by phagosomes ( Ding et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Integrative Analyses and Verification of the Expression and Prognostic Significance for RCN1 in Glioblastoma Multiforme

Chen

Liang

et al. 2021

Front. Mol. Biosci.

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Glioblastoma multiform is a lethal primary brain tumor derived from astrocytic, with a poor prognosis in adults. Reticulocalbin-1 (RCN1) is a calcium-binding protein, dysregulation of which contributes to tumorigenesis and progression in various cancers. The present study aimed to identify the impact of RCN1 on the outcomes of patients with Glioblastoma multiforme (GBM). The study applied two public databases to require RNA sequencing data of Glioblastoma multiform samples with clinical data for the construction of a training set and a validation set, respectively. We used bioinformatic analyses to determine that RCN1 could be an independent factor for the overall survival of Glioblastoma multiform patients. In the training set, the study constructed a predictive prognostic model based on the combination of RCN1 with various clinical parameters for overall survival at 0.5-, 1.0-, and 1.5-years, as well as developed a nomogram, which was further validated by validation set. Pathways analyses indicated that RCN1 was involved in KEAS and MYC pathways and apoptosis. In vitro experiments indicated that RCN1 promoted cell invasion of Glioblastoma multiform cells. These results illustrated the prognostic role of RCN1 for overall survival in Glioblastoma multiform patients, indicated the promotion of RCN1 in cell invasion, and suggested the probability of RCN1 as a potential targeted molecule for treatment in Glioblastoma multiform.

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Reticulocalbin-1 knockdown increases the sensitivity of cells to Adriamycin in nasopharyngeal carcinoma and promotes endoplasmic reticulum stress-induced cell apoptosis

Abstract: 2020) Reticulocalbin-1 knockdown increases the sensitivity of cells to Adriamycin in nasopharyngeal carcinoma and promotes endoplasmic reticulum stress-induced cell apoptosis,

Cited by 23 publications

References 31 publications

EGFRvIII Promotes Cell Survival during Endoplasmic Reticulum Stress through a Reticulocalbin 1-Dependent Mechanism

EGFRvIII Promotes Cell Survival during Endoplasmic Reticulum Stress through a Reticulocalbin 1-Dependent Mechanism

RCN1 induces sorafenib resistance and malignancy in hepatocellular carcinoma by activating c-MYC signaling via the IRE1α–XBP1s pathway

Integrative Analyses and Verification of the Expression and Prognostic Significance for RCN1 in Glioblastoma Multiforme

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