Suppression of pancreatic adenocarcinoma upregulated factor (PAUF) increases the sensitivity of pancreatic cancer to gemcitabine and 5FU, and inhibits the formation of pancreatic cancer stem like cells

Cho, Jae Hee; Kim, Sun A.; Park, Soo Been; Kim, Hee Man; Song, Si Young

doi:10.18632/oncotarget.19458

Cited by 17 publications

(21 citation statements)

References 28 publications

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“…These alternations result not only in chemotherapeutic efflux from cells, but also accelerate the formation of deoxyribonucleotides from ribonucleotides, which supports proliferation of cancer cells. Moreover, PAUF seems to take part in the activation of transcription of another CSC marker, namely CD133 [165]. In a previous study of this CSC marker, that is CD133, gemcitabine decreased only the viability of CD133-cells at higher concentrations, no therapeutic effects were observed among CD133+ PC cells regardless of the drug concentration used [42,47,53,166].…”

Section: Csc As a Cause Of Resistance To Standard Chemotherapy In Panmentioning

confidence: 89%

“…The latest studies have additionally shown that not only CD44+ PC CSC but also CD24+CD44+ESA+ and CD24+ cells are resistant to gemcitabine [162] [140,163,164]. In these cells there additional mechanisms have been detected for both gemcitabine and 5 fluorouracil resistance related to pancreatic adenocarcinoma up-regulated factor (PAUF), which increased the mRNA expression of multidrug resistant protein 5 (MRP5) and ribonucleotide reductase M2 (RRM2) [165]. These alternations result not only in chemotherapeutic efflux from cells, but also accelerate the formation of deoxyribonucleotides from ribonucleotides, which supports proliferation of cancer cells.…”

Section: Csc As a Cause Of Resistance To Standard Chemotherapy In Panmentioning

confidence: 99%

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Markers of pancreatic cancer stem cells and their clinical and therapeutic implications

et al. 2019

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Pancreatic cancer (PC) is the fourth most common cause of death among all cancers. Poor prognosis of PC may be caused by a prevalence of cancer stem cells (CSCs). CSCs are a population of cancer cells showing stem cell-like characteristics. CSCs have the ability to self-renew and may initiate tumorigenesis. PC CSCs express markers such as CD133, CD24, CD44, DCLK1, CXCR4, ESA, Oct4 and ABCB1. There is a wide complexity of interaction and relationships between CSC markers in PC. These markers are negative prognostic factors and are connected with tumor recurrence and clinical progression. Additionally, PC CSCs are resistant to treatment with gemcitabine. Thus, most current therapies for PC are ineffective. Numerous studies have shown, that targeting of these proteins may increase both disease-free and overall survival in PC.

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Section: Csc As a Cause Of Resistance To Standard Chemotherapy In Panmentioning

confidence: 89%

Section: Csc As a Cause Of Resistance To Standard Chemotherapy In Panmentioning

confidence: 99%

Markers of pancreatic cancer stem cells and their clinical and therapeutic implications

et al. 2019

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“…Additionally, they have also revealed that prostate cancer cell sphere formation was markedly suppressed by wild-type p53. Alternatively, Cho et al (26) successfully generated spheres from the adherent pancreatic cancer CFPAC-1 and CAPAN-1 cells bearing p53 mutation in serum-free medium. Based on their observations, CFPAC-1 spheres highly expressed pro-oncogenic PAUF (pancreatic adenocarcinoma upregulated factor) relative to the adherent CFPAC-1 cells and PAUF gene silencing resulted in a decrease in the number of spheres and an enhancement of chemotherapeutic response to GEM in association with downregulation of MRP5 (multidrug resistant protein 5) and RPM2 (ribonucleotide reductase M2).…”

Section: Discussionmentioning

confidence: 99%

Impact of RUNX2 gene silencing on the gemcitabine sensitivity of p53‑mutated pancreatic cancer MiaPaCa‑2 spheres

et al. 2018

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Recently, it has been well‑recognized that the response toward anticancer drugs differs between two‑ and three‑dimensional (2D and 3D) in vitro cancer cell growth models. In the present study, we have demonstrated that, similar to the conventional 2D monolayer culture systems which often lack in vivo physiological insights, RUNX2 gene silencing increases the gemcitabine (GEM) sensitivity of the 3D spheres generated from p53‑mutated pancreatic cancer MiaPaCa‑2 cells. According to our results, MiaPaCa‑2 cells, but not p53‑wild‑type pancreatic cancer SW1990 cells efficiently formed sphere structures in serum‑free sphere‑forming medium. Although GEM treatment caused a marked induction of TAp73/TAp63 in MiaPaCa‑2 spheres accompanied by the transcriptional activation of p53 family‑target genes such as p21WAF1 and NOXA, only 20% of cells underwent cell death. Under these experimental conditions, mutant p53 expression level was increased in response to GEM and RUNX2 remained unchanged at the protein level regardless of GEM exposure, which may suppress the pro‑apoptotic activity of TAp73/TAp63. Notably, RUNX2 gene silencing markedly augmented GEM‑mediated cell death of MiaPaCa‑2 spheres compared to that of non‑depleted ones. Expression analyses revealed that forced depletion of RUNX2 further stimulated GEM‑induced upregulation of TAp63 as well as its downstream target genes such as p21WAF1 and NOXA. In summary, our observations strongly indicated that, similarly to 2D monolayer culture, RUNX2 gene silencing increased GEM sensitivity of MiaPaCa‑2 spheres and highlighted the therapeutic potential of RUNX2 in pancreatic cancer with p53 mutation.

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“…Chemoresistance is a major hindrance to successful treatment of many tumors. Thus, it is crucial to elucidate the mechanisms of chemoresistance and develop therapeutic strategies to resensitize cancer cells to chemotherapy [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

NRF2 Knockdown Resensitizes 5-Fluorouracil-Resistant Pancreatic Cancer Cells by Suppressing HO-1 and ABCG2 Expression

Kim

Lee

et al. 2020

IJMS

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Chemoresistance is a leading cause of morbidity and mortality in patients with pancreatic cancer and remains an obstacle to successful treatment. The antioxidant transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (NRF2), which plays important roles in tumor angiogenesis and invasiveness, is upregulated in pancreatic ductal adenocarcinoma (PDAC), where it correlates with poor survival. Here, we investigated the role of NRF2 in two 5-Fluourouracil-resistant (5-FUR) PDAC cell lines: BxPC-3 and CFPAC-1. Levels of NRF2 and antioxidants, such as heme oxygenase 1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), and superoxide dismutase 2 (SOD2), were higher in the chemoresistant cells than in their chemosensitive counterparts. Expression of epithelial mesenchymal transition (EMT) markers, stemness markers, including Nanog, Oct4, and CD133, and that of the drug transporter ATP binding cassette, subfamily G, member A2 (ABCG2) was also upregulated in 5-FUR PDAC cells. NRF2 knockdown reversed 5-FU resistance of PDAC cells via suppression of ABCG2 and HO-1. In summary, these data indicate that NRF2 is a potential target for resensitizing 5-FUR PDAC cells to 5-FU to improve treatment outcomes in patients with pancreatic cancer.

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Suppression of pancreatic adenocarcinoma upregulated factor (PAUF) increases the sensitivity of pancreatic cancer to gemcitabine and 5FU, and inhibits the formation of pancreatic cancer stem like cells

Cited by 17 publications

References 28 publications

Markers of pancreatic cancer stem cells and their clinical and therapeutic implications

Markers of pancreatic cancer stem cells and their clinical and therapeutic implications

Impact of RUNX2 gene silencing on the gemcitabine sensitivity of p53‑mutated pancreatic cancer MiaPaCa‑2 spheres

NRF2 Knockdown Resensitizes 5-Fluorouracil-Resistant Pancreatic Cancer Cells by Suppressing HO-1 and ABCG2 Expression

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