Retracted: Antiproliferative Effects of Matricine in Gemcitabine-Resistant Human Pancreatic Carcinoma Cells Are Mediated via Mitochondrial-Mediated Apoptosis, Inhibition of Cell Migration, Invasion Suppression, and Mammalian Target of Rapamycin (mTOR)-TOR/PI3K/AKT Signalling Pathway.

An editorial decision has been made to retract this manuscript due to breach of publishing guidelines, following the identification of non-original and manipulated figures. Reference: Kaifeng Fang, Li Wang, LuJia Chen, Tao Liu, Zhi Fang: Antiproliferative Effects of Matricine in Gemcitabine-Resistant Human Pancreatic Carcinoma Cells Are Mediated via Mitochondrial-Mediated Apoptosis, Inhibition of Cell Migration, Invasion Suppression, and Mammalian Target of Rapamycin (mTOR)-TOR/PI3K/AKT Signalling Pathway. Med Sci Monit 2019; 25:2943-2949. 10.12659/MSM.914244.

Antiproliferative Effects of Matricine in Gemcitabine-Resistant Human Pancreatic Carcinoma Cells Are Mediated via Mitochondrial-Mediated Apoptosis, Inhibition of Cell Migration, Invasion Suppression, and Mammalian Target of Rapamycin (mTOR)-TOR/PI3K/AKT Signalling Pathway.

BACKGROUND Pancreatic cancer is a major cause of mortality worldwide. Inefficient drugs, their adverse effects, and the development of drug resistance make it difficult to curb the growing incidence of pancreatic cancer. Against this backdrop, the development new drug regimens with no or negligible adverse effects is imperative. We assessed the anticancer effects of a plant-derived sesquiterpene - matricine - against capan-2 pancreatic cancer cells. MATERIAL AND METHODS Cell viability was determined by MTT assay. AO/EB, DAPI, and annexin V/PI staining were used to detect apoptosis. Transwell assays were used for monitoring of cell migration and invasion. Immunoblotting was used to examine the expression of proteins. RESULTS The results showed that matricine halted the proliferation of capan-2 cells, with minimal toxic effects on normal pancreatic cells. The anticancer effects were due to the induction of apoptotic cell death, which was allied with activation of caspases 3 and 9, upregulation of Bax, and downregulation of Bcl-2. Moreover, matricine suppressed the migration and invasive abilities of pancreatic cancer cells at IC50. We also assessed the effects of matricine on the mTOR/PI3K/AKT signalling pathway. We found that matricine efficiently blocked this pathway, suggesting the anticancer potential of matricine. CONCLUSIONS Matricine induced antiproliferative effects in capan-2 human pancreatic cancer cells through inducing apoptosis, caspase activation, inhibition of cell migration and invasion, and blocking the mTOR/PI3K/AKT signalling pathway.

A reciprocal feedback of Myc and lncRNA MTSS1-AS contributes to extracellular acidity-promoted metastasis of pancreatic cancer.

Rationale: Previous studies have reported on the role of extracellular acidity in the metastasis of numerous cancers. However, the involvement of long noncoding RNA (lncRNA) in the extracellular acidity-induced cancer metastasis of pancreatic cancer (PC) remains unclear. Methods: Different expression levels of lncRNAs in PC cells under normal and acidic conditions were compared by RNA sequencing (RNA-seq). The effects of antisense lncRNA of metastasis suppressor 1 (MTSS1-AS) on acidic PC cells were assessed by gain- and loss-of-function experiments. Fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down, Western blot, luciferase reporter, and Chromatin immunoprecipitation assays were employed to determine the regulatory mechanisms of MTSS1-AS in the acidity-induced metastasis of PC cells. The expression of MTSS1-AS and associated pathways were compared in PC samples and peritumoral normal tissues. Results: RNA-seq demonstrated that MTSS1-AS was significantly downregulated in pancreatic cells cultured with the acidic medium. The overexpression of MTSS1-AS remarkably inhibited the acidity-promoted metastasis of PC cells by upregulating the expression of its sense gene metastasis suppressor 1 (MTSS1). Mechanistically, MTSS1-AS scaffolded the interaction between E3 ubiquitin-protein ligase STIP1 homology and U-box containing protein 1 (STUB1) and transcription regulator myeloid zinc finger 1 (MZF1), leading to ubiquitination-mediated degradation of MZF1. Further, MZF1 inhibited the expression of MTSS1 by binding to the MTSS1 promoter. Thus, the acidity-reduced MTSS1-AS facilitated the stability of MZF1 and its inhibitory effect on MTSS1 transcription, thereby promoting the metastasis of PC cells under acidic conditions. Moreover, MTSS1-AS was transcriptionally repressed by the binding of MYC proto-oncogene (Myc) with initiator (Inr) elements of the MTSS1-AS promoter. Meanwhile, MTSS1-AS mutually repressed the expression of Myc by impairing the MZF1-mediated transcription activation of Myc, thereby forming a negative feedback loop between MTSS1-AS and Myc in acidic PC cells. In accordance with the experimental results, MTSS1-AS and MTSS1 were downregulated in PC and correlated with poor overall survival. Conclusions: The results implicated that a reciprocal feedback loop between Myc and MTSS1-AS contributed to the extracellular acidity-promoted metastasis of PC, and indicated that MTSS1-AS was a valuable biomarker and therapeutic target for PC.

microRNA-1225 inhibit apoptosis of pancreatic cancer cells via targeting JAK1.

The microRNA miRNA-1225-5p (miR-1225) is known as an essential modulator of the development of multiple cancers and other biological reactions. However, the understanding of its contribution to pancreatic cancer (PC) is insufficient. The effects of miR-1225 on PC cell survival and tumorigenesis in vivo as well as on the modulation of cell apoptosis were investigated. The expression of miR-1225 was upregulated in 20 human LC samples from acute myeloid leukemia patients with adverse prognosis and poor responses to therapy as well as in several human PC cell lines, as compared to that in healthy tissues, normal tissues, and normal pancreatic cells. In contrast, Janus kinase 1 (JAK1) expression was downregulated in human-derived PC samples and PC cell lines. EdU staining demonstrated that the aberrant expression of miR-1225 impaired the proliferation and survival of these two PC cell lines. The depletion of miR-1225 expression increased the apoptosis of both PANC-1 and AsPC-1 cells, as revealed by the TdT-mediated dUTP nick end labeling (TUNEL) staining and flow cytometry results. The results of dual-luciferase reporter assay indicated that miR-1225 targeted the 3'-untranslated region of JAK1 for silencing. Silencing of JAK1 expression counteracted the suppressive influence of miR-1225 depletion in PC cells. Thus, these results offer an insight into the biological and molecular mechanisms underlying the development of PC and provide potential strategies for PC treatment.

Relationship between carbachol hyperstimulation-induced pancreatic intracellular trypsinogen and NF-kappa B activation in rats in vitro.

The relationship between intracellular trypsinogen activation and NF-kappa B activation in rat pancreatic acinar cells induced by M3 cholinergic receptor agonist (carbachol) hyperstimulation was studied. Rat pancreatic acinar cells were isolated, cultured and treated with carbachol, the active protease inhibitor (pefabloc) and NF-kappa B inhibitor (PDTC) in vitro. Intracellular trypsin activity was measured by using a fluorogenic substrate. The activity of NF-kappa B was monitored by using electrophoretic mobility shift assay. The results showed that after pretreatment with 2 mmol/L pefabloc, the activities of trypsin and NF-kappa B in pancreatic acinar cells treated with high concentrations of carbachol (10(-3) mol/L) in vitro was significantly decreased as compared with control group (P<0.01). The addition of 10(-2) mol/L PDTC resulted in a significant decrease of NF-kappa B activities in pancreatic acinar cells after treated with high concentrations of carbachol (10(-3) mol/L) in vitro, but the intracellular trypsinogen activity was not obviously inhibited (P>0.05). It was concluded that intracellular trypsinogen activation is likely involved in the regulation of high concentrations of carbachol-induced NF-kappa B activation in pancreatic acinar cells in vitro. NF-kappa B activation is likely not necessary for high concentrations of carbachol-induced trypsinogen activation in pancreatic acinar cells in vitro.

Relationship between carbachol hyperstimulation-induced pancreatic acinar cellular injury and trypsinogen or NF-kappaB activation in rats in vitro.

The relationship between M3 cholinergic receptor agonist (carbachol) hyperstimulation-induced pancreatic acinar cellular injury and trypsinogen activation or NF-kappaB activation in rats was studied in vitro. Rat pancreatic acinar cells were isolated, cultured and treated with carbachol, the active protease inhibitor (pefabloc), and NF-kappaB inhibitor (PDTC) in vitro. Intracellular trypsin activity was measured by using a fluorogenic substrate. The cellular injury was evaluated by measuring the leakage of LDH from pancreatic acinar cells. The results showed that as compared with control group, 10(-3) mol/L carbachol induced a significant increase of the intracellular trypsin activity and the leakage of LDH from pancreatic acinar cells. Pretreatment with 2 mmol/L pefabloc could significantly decrease the activity of trypsin and the leakage of LDH from pancreatic acinar cells (P < 0.01) following the treatment with a high concentration of carbachol (10(-3) mol/L) in vitro. The addition of 10(-2) mol/L PDTC didn't result in a significant decrease in the activity of trypsin and the leakage of LDH from pancreatic acinar cells treated with a high concentration of carbachol (10(-3) mol/L) in vitro (P > 0.05). It was concluded that intracellular trypsinogen activation is likely involved in pancreatic acinar cellular injury induced by carbachol hyperstimulation in vitro. NF-kappaB activation may not be involved in pancreatic acinar cellular injury induced by carbachol hyperstimulation in vitro.