Activation of the PERK-ATF4 pathway promotes chemo-resistance in colon cancer cells

Su, Zhong; Yu, Xiaofu; Ma, Yuan; Lv, Wenzhen; Feng, Tingting; Bai, Rui; Huang, Zhong

doi:10.1038/s41598-019-39547-x

Cited by 47 publications

(39 citation statements)

References 35 publications

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“…ATF4 has been observed to serve important roles in ER stress-induced apoptosis (30) and radiotherapy (31) or chemotherapy sensitivity (32). In CRC cells, the activation of the PERK/ATF4 signaling pathway promoted resistance to 5-fluorouracil (33) and increased expression levels of ATF4 were associated with glucose deprivation-induced chemoresistance (34). In prostate cancer, ATF4 protein expression levels were increased in the cancer tissue compared with benign prostate tissue (35) and similarly, in breast cancer, ATF4 expression levels were increased in HER2 + breast cancer, which promoted cell migration through the activation of zinc finger E-box binding homeobox 1 (ZEB1) and the downregulation of E-cadherin (36).…”

Section: Discussionmentioning

confidence: 99%

Thapsigargin promotes colorectal cancer cell migration through upregulation of lncRNA MALAT1

Jiang

Wang

et al. 2020

Oncol Rep

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Colorectal cancer (CRC) is the third most common tumor in the world; however, the role and mechanism of endoplasmic reticulum (ER) stress in CRC metastasis remains largely unclear. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA), which has previously been associated with CRC metastasis. It has been suggested that ER stress pathways regulate lncRNA expression; however, the effect of ER stress on MALAT1 expression in cancer is unknown. The present study aimed to investigate the relationship between ER stress pathways, MALAT1 expression and cell migration in CRC cells. ER stress was induced by thapsigargin (TG); low dose TG induced the migration of HT29 and HCT116 cells, but not SW1116 and SW620 cells. This effect was associated with increased expression levels of MALAT1, as the knockdown of MALAT1 prevented TG-induced cell migration. TG-induced MALAT1 expression was associated with inositol-requiring enzyme 1 (IRE1) expression and activation of the protein kinase R (PKR)-like ER kinase (PERK) signaling pathway. X-box-binding protein 1 (XBP1) and activating transcription factor 4 (ATF4) binding sites were predicted to be located in the MALAT1 gene promoter regions and the expression of MALAT1 was positively associated with XBP1 and ATF4 expression levels in CRC tissue samples. Thus, these findings indicated that ER stress may promote the migration of CRC cells and contribute to the progression of CRC through the activation of the IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways. In conclusion, to the best of our knowledge, this study is the first report that lncRNA MALAT1 expression is regulated by the IRE1/XBP1 pathway in CRC.

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Section: Discussionmentioning

confidence: 99%

Thapsigargin promotes colorectal cancer cell migration through upregulation of lncRNA MALAT1

Jiang

Wang

et al. 2020

Oncol Rep

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“…ER stress triggers the UPR in carcinogenesis (Mcgrath et al, 2018;Liu J. et al, 2019;Siwecka et al, 2019). On one hand, ER stress promotes cell survival and induces drug resistance (Rzymski et al, 2009;Pandey et al, 2019;Shi et al, 2019), and on the other hand, long-term ER stress can become pro-apoptotic (Han et al, 2013;Liu Y. S. et al, 2019). UPR consists of three major signaling pathways mediated by inositol-requiring enzyme 1 (IRE-1), ATF6, and PERK.…”

Section: Discussionmentioning

confidence: 99%

CCT020312 Inhibits Triple-Negative Breast Cancer Through PERK Pathway-Mediated G1 Phase Cell Cycle Arrest and Apoptosis

Zhou

et al. 2020

Front. Pharmacol.

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Triple-negative breast cancer (TNBC) has a poor prognosis due to the lack of specific therapeutic targets. CCT020312, a selective eukaryotic translation initiation factor 2 alpha (eIF2a)/protein kinase RNA-like endoplasmic reticulum kinase (PERK) activator, may have a potent anti-tumor effect. In the present study, we examined the effects of CCT020312 on TNBC and explored the underlying mechanism. We found that CCT020312 inhibited the viability of TNBC cell lines, MDA-MB-453 and CAL-148, by inducing apoptosis and G1 phase cell cycle arrest. CCT020312 decreased the protein levels of cyclin-dependent kinase 4 (CDK4), CDK6, cyclin D1, and B-cell lymphoma 2 (Bcl-2) and increased the levels of Bcl-2-associated X protein (Bax) and cleaved poly (ADP-ribose) polymerase (PARP) compared with those in the control. CCT020312 activated PERK/eIF2a/activating transcription factor 4 (ATF4)/CCAAT-enhancer binding protein (C/EBP) homologous protein transcription factor (CHOP) signaling and inhibited protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) signaling. Furthermore, CCT020312 inhibited tumor growth in an MDA-MB-453 orthotopic xenograft mouse model by activating the PERK/eIF2a/ATF4/CHOP pathway and inhibiting the AKT/mTOR pathway. Thus, our study shows that CCT020312 may be a potential drug candidate for TNBC treatment.

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“…UPR may act as a key driver in resistance to chemotherapy [36,37]. A new encouraging research nds that activation of the PERK branch with UPR is required for colon cancer cells surviving from treatment of 5-uorouracil, the usage of PERK inhibitor synergizes with 5-FU could suppress the growth of colon cancer cells in vivo [38].…”

Section: Discussionmentioning

confidence: 99%

Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastric Cancer

Zhang

Zhao

Zhang

et al. 2020

Preprint

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Background: Prolyl 4-hydroxylase, beta polypeptide (P4HB) and Glucose‑regulated protein 78 (GRP78) are represent for poor prognosis of various cancers. However, rare research investigate the correlation of them in cancer. This study aimed to investigate the correlation and prognostic value of P4HB and GRP78 expression along with clinical features in gastric cancer (GC).Methods: A total of 150 GC tissue samples separately evaluated P4HB and GRP78 protein expression by immunohistochemistry. Association of P4HB and GRP78 expression with clinicopathological features was analyzed. Bioinformatics analyses were performed to find correlation between mRNAs and pathways. Kaplan-Meier analyses were taken to compare survival curves. Univariate and multivariate Cox regression models used to analyze the impact of prognostic factors on overall survival (OS). A prognostic nomogram was constructed based on the multivariate Cox regression model, and compared to TNM stage in discrimination ability and clinical usefulness.Results: P4HB and GRP78 expression were both associated with tumor invasion and lymph node metastasis. P4HB protein positively correlated with GRP78, as well as the same tendency of mRNAs in both GC tissue and cell databases. Bioinformatics analyses indicated that P4HB and GRP78 may be associated with protein folding and response to ER stress, and the protein processing in ER pathway. High single or co-expression of P4HB and GRP78 represented for a shorter OS. When stratified by postoperative adjuvant chemotherapy, the high co-expression was only related to unfavorable prognosis of with chemotherapy group, especially in advanced stage. Multivariate Cox regression analysis identified co-expression of P4HB and GRP78 as an independent prognostic factor for OS. The nomogram including the co-expression was better than TNM stage in discrimination ability and clinical usefulness through the receiver operating characteristic (ROC) and decision curve analysis (DCA) curves.Conclusion: P4HB was positively correlated with GRP78 expression, co-expression of them was an independent prognostic factor, could serve as a predictive marker for GC patients with postoperative adjuvant chemotherapy in advanced stage.

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Activation of the PERK-ATF4 pathway promotes chemo-resistance in colon cancer cells

Cited by 47 publications

References 35 publications

Thapsigargin promotes colorectal cancer cell migration through upregulation of lncRNA MALAT1

Thapsigargin promotes colorectal cancer cell migration through upregulation of lncRNA MALAT1

CCT020312 Inhibits Triple-Negative Breast Cancer Through PERK Pathway-Mediated G1 Phase Cell Cycle Arrest and Apoptosis

Clinic Correlation and Prognostic Value of P4HB and GRP78 Expression in Gastric Cancer

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