Combination treatment of all-trans retinoic acid (ATRA) and γ-secretase inhibitor (DAPT) cause growth inhibition and apoptosis induction in the human gastric cancer cell line

Patrad, Elham; Niapour, Ali; Farassati, Faris; Amani, Mojtaba

doi:10.1007/s10616-018-0199-3

Cited by 20 publications

(16 citation statements)

References 55 publications

(79 reference statements)

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“…In our validating study, we confirmed that GC cell line with amplified ERBB2 and RARA (NCI-N87) was sensitive to Lapatinib relative to GC cell without amplified ERBB2 and RARA (MKN-45). The sensitivity to ATRA on both cell lines did not show significant difference, which may attribute to some alternative pathways for ATRA-mediated apoptosis ( Patrad et al, 2018 ). We found that Lapatinib and ATRA could synergistically inhibit cell growth in NCI-N87 cell, but not in MKN-45 cell.…”

Section: Discussionmentioning

confidence: 99%

Cross-Database Analysis Reveals Sensitive Biomarkers for Combined Therapy for ERBB2+ Gastric Cancer

et al. 2018

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Exploring ERBB2-related pathways will help us finding sensitive molecules and potential combined therapeutic targets of ERBB2-targeted therapy for ERBB2+ gastric cancer (GC). In this study, we performed a cross-databases study focused on ERBB2+ GC. The data of ERBB2+ GC deposited in the cancer genome atlas (TCGA), gene expression omnibus (GEO), InBio MapTM, cancer cell line encyclopedia (CCLE), and cancer therapeutics response portal (CTRP) were analyzed. The correlation of expression levels of candidate and IC50 of candidate genes-targeted drugs were verified on NCI-N87 and MKN-45 GC cell lines. We found that RARA, THRA, CACNB1, and TOP2A are drug sensitive biomarkers of ERBB2-targeted treatment with FDA-approved drugs. All these genes act through Myc signaling pathway. Myc is the downstream hub gene of both ERBB2 and RARA. The expression of RARA, THRA, and CACNB1 were negatively correlated with Myc activation, while ERBB2 and TOP2A positively correlated with Myc activation. SH3BGRL3, SH3BGRL, and NRG2 were identified as potential ligands of ERBB2. The ERBB2+ GC with RARA amplification demonstrated better prognosis than those without RARA amplification, while overexpression of NRG2 and SH3BGRL correlated with poor prognosis in ERBB2+ GC. About 90% of ERBB2+ GC was compatible with chromosome instability (CIN) subtype of TCGA, which overlaps with intestinal-type GC in Lauren classification. In validating experiments, combination of Lapatinib and all-trans retinoic acid (ATRA) synergistically suppresses cell growth, and accompanied by decreased expression of MYC. In conclusions, we identified several predicting biomarkers for ERBB2-targeted therapy and corresponding histological features of ERBB2+ GC. Combination of ERBB2 antagonist or RARA agonist may be effective synergistic regimens for ERBB2+ GC.

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Section: Discussionmentioning

confidence: 99%

Cross-Database Analysis Reveals Sensitive Biomarkers for Combined Therapy for ERBB2+ Gastric Cancer

et al. 2018

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“…therapeutic potential in breast cancer, colorectal cancer, and gastric cancer (39)(40)(41). However, little research exists investigating the relationship between ATRA and NPC.…”

Section: Ra Is a Metabolic Intermediate Of Vitamin A And Atramentioning

confidence: 99%

APLNR is involved in ATRA‐induced growth inhibition of nasopharyngeal carcinoma and may suppress EMT through PI3K‐Akt‐mTOR signaling

Liu¹,

Liu²,

Chen³

et al. 2019

FASEB j.

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The apelin receptor (APLNR) is a GPCR involved in many pathophysiological processes; however, the correlation between APLNR expression and nasopharyngeal carcinoma (NPC) has not been reported. In this study, we used cDNA microarray data to determine APLNR expression levels in NPC tissues. We found that APLNR expression was reduced in NPC tissues compared with noncancerous nasopharyngeal epithelial tissues. Subsequently, a large‐scale sample of 1015 tissues was used to validate this discovery and explore the relationship between APLNR expression and prognosis of NPC. Expression levels of APLNR in NPC tissues were indeed down‐regulated. Furthermore, positive expression of APLNR in NPC predicted a better prognosis (disease‐free survival: P = 0.001; overall survival: P < 0.001). Moreover, ingenuity pathway analysis revealed that an indirect interaction existed between APLNR and retinoic acid (RA) in the cancer regulatory network. Consistently, after treatment with all‐trans‐RA (ATRA), we found that APLNR was significantly up‐regulated in NPC cell lines (5‐8F and HNE1), and proliferation of NPC cells was inhibited. Cell cycle arrest occurred in the G0/G1 phase. In contrast, knockdown of APLNR diminished ATRA‐induced growth inhibition of NPC cells. In addition, we surprisingly found that APLNR also played an important role in migration and invasion of NPC. Wound‐healing and Transwell assays revealed that APLNR overexpression led to reduced migratory and invasive properties in 2 NPC cell lines. Western blot results revealed that hallmarks of epithelial‐mesenchymal transition (EMT) were altered as well, suggesting that APLNR was capable of inhibiting EMT in NPC cells. Our study further demonstrated that low expression of APLNR promoted EMT in NPC cells by activating the PI3K‐protein kinase B‐mammalian target of rapamycin signaling pathway. Taken together, our data suggest that APLNR could potentially predict prognosis for patients with NPC and inhibit proliferation, migration, invasion, and EMT in nasopharyngeal cancer cells.—Liu, Y., Liu, Q., Chen, S., Liu, Y., Huang Y., Chen, P., Li, X., Gao, G., Xu, K., Fan, S., Zeng Z., Xiong W., Tan, M., Li, G., Zhang W. APLNR is involved in ATRA‐induced growth inhibition of nasopharyngeal carcinoma and may suppress EMT through PI3K‐Akt‐mTOR signaling. FASEB J. 33, 11959‐11972 (2019). http://www.fasebj.org

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“…To further understand the effect of ATRA on GC, studies have been conducted and three main anti-cancerous effect of this molecule have been identified: (i) inhibition of cell cycle and induction of cell differentiation [ 88 , 89 , 90 , 91 , 92 ]; (ii) pro-apoptotic action [ 88 , 93 , 94 , 95 ], and (iii) inhibition of CSCs properties [ 88 , 96 , 97 ] ( Table 2 ).…”

Section: Atra On Gc Modelsmentioning

confidence: 99%

Efficiency of All-Trans Retinoic Acid on Gastric Cancer: A Narrative Literature Review

Bouriez

Giraud

Gronnier

et al. 2018

IJMS

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Gastric cancer (GC) is the third leading cause of cancer-related death worldwide with a five-year survival rate of around 25%, and 4% when diagnosed at a metastatic stage. Cancer stem cells (CSC) have recently been characterized as being responsible for resistance to radio/chemotherapies and metastasis formation, opening up perspectives for new targeted therapies. Those CSCs express biomarkers such as cluster of differentiation 44 (CD44) and display high aldehyde dehydrogenase activity that converts vitamin A-derived retinal into retinoic acids. All-trans retinoic acid (ATRA), which has pro-differentiating properties, has revolutionized the prognosis of acute promyelotic leukemia by increasing its remission rate from 15% to 85%. Recent studies have started to show that ATRA also has an anti-tumoral role on solid cancers such as GC. The purpose of this review is therefore to summarize the work that evaluated the effects of ATRA in GC and to evaluate whether its anti-cancerous action involves gastric CSCs targeting. It has been demonstrated that ATRA can block the cell cycle, enhance apoptosis, and decrease gastric CSCs properties in GC cell lines, tumorspheres, and patient-derived xenograft mice models. Therefore, retinoids and new synthetic retinoids seem to be a promising step forward in targeted therapy of gastric CSC in combination with existing chemotherapies. Future studies should probably focus on these points.

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Combination treatment of all-trans retinoic acid (ATRA) and γ-secretase inhibitor (DAPT) cause growth inhibition and apoptosis induction in the human gastric cancer cell line

Cited by 20 publications

References 55 publications

Cross-Database Analysis Reveals Sensitive Biomarkers for Combined Therapy for ERBB2+ Gastric Cancer

Cross-Database Analysis Reveals Sensitive Biomarkers for Combined Therapy for ERBB2+ Gastric Cancer

APLNR is involved in ATRA‐induced growth inhibition of nasopharyngeal carcinoma and may suppress EMT through PI3K‐Akt‐mTOR signaling

Efficiency of All-Trans Retinoic Acid on Gastric Cancer: A Narrative Literature Review

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