Knockdown of IRE1ɑ suppresses metastatic potential of colon cancer cells through inhibiting FN1-Src/FAK-GTPases signaling

et al. 2020

J Exp Clin Cancer Res

Background Our previous study showed that calreticulin (CRT) promoted EGF-induced epithelial-mesenchymal transition (EMT) in pancreatic cancer (PC) via Integrin/EGFR-ERK/MAPK signaling. We next investigated the novel signal pathway and molecular mechanism involving the oncogenic role of CRT in PC. Methods We investigated the potential role and mechanism of CRT in regulating intracellular free Ca2+ dependent acute and chronic endoplasmic reticulum stress (ERS)-induced EMT in PC in vitro and vivo. Results Thapsigargin (TG) induced acute ERS via increasing intracellular free Ca2+ in PC cells, which was reversed by CRT silencing. Additionally, CRT silencing inhibited TG-induced EMT in vitro by reversing TG-induced changes of the key proteins in EMT signaling (ZO-1, E-cadherin and Slug) and ERK/MAPK signaling (pERK). TG-promoted cell invasion and migration was also rescued by CRT silencing but enhanced by IRE1α silencing (one of the key stressors in unfolded protein response). Meanwhile, CRT was co-immunoprecipitated and co-localized with IRE1α in vitro and its silencing led to the chronic ERS via upregulating IRE1α independent of IRE1-XBP1 axis. Moreover, CRT silencing inhibited IRE1α silencing-promoted EMT, including inhibiting the activation of EMT and ERK/MAPK signaling and the promotion of cell mobility. In vivo, CRT silencing decreased subcutaneous tumor size and distant liver metastasis following with the increase of IRE1α expression. A negative relationship between CRT and IRE1α was also observed in clinical PC samples, which coordinately promoted the advanced clinical stages and poor prognosis of PC patients. Conclusions CRT promotes EMT in PC via mediating intracellular free Ca2+ dependent TG-induced acute ERS and IRE1α-mediated chronic ERS via Slug and ERK/MAPK signaling.

Section: Discussionmentioning

confidence: 59%

Calreticulin promotes EMT in pancreatic cancer via mediating Ca2+ dependent acute and chronic endoplasmic reticulum stress

et al. 2020

J Exp Clin Cancer Res

“…However, IRE1α overexpression was associated with the resistant mechanism to osimertinib in NSCLC HCC827/OSIR Cells 68 . Similarly, several studies have shown that IRE1α plays a contradictory role in colon cancer cells [69][70][71][72] . We next found that CRT was co-immunoprecipitated and co-localized with IRE1α in vitro and its stable silencing caused chronic ERS by speci cally activating IRE1α independent of IRE1/XBP1 axis.…”

Section: Discussionmentioning

confidence: 93%

Calreticulin promotes EMT in pancreatic cancer via mediating Ca2+ dependent acute and chronic endoplasmic reticulum stress

et al. 2020

Preprint

Background: Our previous study showed that calreticulin (CRT) promoted EGF-induced epithelial-mesenchymal transition (EMT) in pancreatic cancer (PC) via Integrin/EGFR-ERK/MAPK signaling. We next investigated the novel signal pathway and molecular mechanism involving the oncogenic role of CRT in PC. Methods: We investigated the potential role and mechanism of CRT in regulating intracellular free Ca2+ dependent acute and chronic endoplasmic reticulum stress (ERS)-induced EMT in PC in vitro and vivo.Results: Thapsigargin (TG) induced acute ERS via increasing intracellular free Ca2+ in PC cells, which was reversed by CRT silencing. Additionally, CRT silencing inhibited TG-induced EMT in vitro by reversing TG-induced changes of the key proteins in EMT signaling (ZO-1, E-cadherin and Slug) and ERK/MAPK signaling (pERK). TG-promoted cell invasion and migration was also rescued by CRT silencing but enhanced by IRE1α silencing (one of the key stressors in unfolded protein response). Meanwhile, CRT was co-immunoprecipitated and co-localized with IRE1α in vitro and its silencing led to the chronic ERS via upregulating IRE1α independent of IRE1-XBP1 axis. Moreover, CRT silencing inhibited IRE1α silencing-promoted EMT, including inhibiting the activation of EMT and ERK/MAPK signaling and the promotion of cell mobility. In vivo, CRT silencing decreased subcutaneous tumor size and distant liver metastasis following with the increase of IRE1α expression. A negative relationship between CRT and IRE1α was also observed in clinical PC samples, which coordinately promoted the advanced clinical stages and poor prognosis of PC patients. Conclusions: CRT promotes EMT in PC via mediating intracellular free Ca2+ dependent TG-induced acute ERS and IRE1α-mediated chronic ERS via Slug and ERK/MAPK signaling.

“…However, IRE1α overexpression was associated with the resistant mechanism to osimertinib in NSCLC HCC827/OSIR Cells 68 . Similarly, several studies have shown that IRE1α plays a contradictory role in colon cancer cells [69][70][71][72] . We next found that CRT was coimmunoprecipitated with IRE1α and its stable silencing caused chronic ERS by speci cally activating IRE1α independent of XBP1.…”

Section: Discussionmentioning

confidence: 93%

Calreticulin Promotes EMT in Pancreatic Cancer via Mediating Ca2+ Dependent Acute and Chronic Endoplasmic Reticulum Stress

et al. 2020

Preprint

Background: Our previous study showed that calreticulin (CRT) promoted EGF-induced epithelial-mesenchymal transition (EMT) in pancreatic cancer (PC) via Integrin/EGFR-ERK/MAPK signaling. We next investigated the novel signaling pathway and molecular mechanism involving the oncogenic role of CRT in PC development. Methods: We investigated the potential role and mechanism of CRT in regulating Ca2+ dependent acute and chronic endoplasmic reticulum stress (ERS)-induced EMT in PC in vitro and vivo.Results: Thapsigargin (TG) induced acute ERS via increasing intracellular free Ca2+ in PC cells, which was reversed by CRT silencing. Additionally, CRT silencing inhibited TG-induced EMT in vitro by reversing TG-induced changes of the key proteins in EMT signaling (ZO-1, E-cadherin and Slug) and ERK/MAPK signaling (pERK), and inhibiting TG-promoted cell invasion and migration. Meanwhile, CRT was coimmunoprecipitated with inositol-requiring enzyme 1α (IRE1α, one of the key stressors in unfolded protein response) in vitro and its silencing led to the chronic ERS via upregulating IRE1α but independent of X-box-binding protein 1 (XBP1). Moreover, CRT silencing inhibited IRE1α silencing-promoted EMT, including inhibiting the activation of EMT and ERK/MAPK signaling and the promotion of cell mobility. In addition, CRT silencing decreased subcutaneous tumor size and distant liver metastasis in vivo. Furthermore, a negative relationship between CRT and IRE1α was observed in vivo and in clinical PC samples, which coordinately promoted the advanced clinical stages and poor prognosis of PC patients. Conclusions: CRT promoted EMT in PC via mediating Ca2+ dependent TG-induced acute ERS and IRE1α-mediated chronic ERS via Slug and ERK/MAPK signaling.