Adjuvant, neoadjuvant, and experimental regimens in overcoming pancreatic ductal adenocarcinoma

Wysocka, Olga; Kulbacka, Julita; Saczko, Jolanta

doi:10.5114/pg.2016.61438

Cited by 8 publications

(7 citation statements)

References 71 publications

(72 reference statements)

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“…Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly malignancies. Despite an improving understanding of its biology and pathogenesis, contemporary treatment regimens are still lacking in terms of efficacy [ 1 ]. Data from recent studies have shown that the occurrence and development of various human tumours are related to the inactivation of tumour-suppressor genes [ 2 – 5 ].…”

Section: Introductionmentioning

confidence: 99%

PDZ-containing 1 acts as a suppressor of pancreatic cancer by regulating PTEN phosphorylation

Wu³

et al. 2017

Oncotarget

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Phosphorylation is a recently established cause of phosphatase and tensin homolog (PTEN) gene inactivation, which leads to defect tumour-suppressor function. In pancreatic cancer, this phenomenon has not been reported. Based on database and clinical sample analyses, we found that PTEN phosphorylation occurs in pancreatic ductal adenocarcinoma patient tissues and cell lines, and we aimed to find a method for dephosphorylation. PDZ-containing 1 (PDZK1), a tumour-associated protein that shares its PDZ-binding sequence with the carboxyl-terminal domain of PTEN, was significantly down-regulated in pancreatic cancer as compared to adjacent non-tumour tissues. In vitro, PDZK1 overexpression reversed the proliferation and migration abilities of pancreatic cancer cells and led to significantly decreased PTEN phosphorylation and AKT phosphorylation by interacting with wild-type PTEN. In addition, a transcription factor-activation assay supported that PDZK1 overexpression enhanced the anti-oncogene function of PTEN by regulating the activities of its downstream transcription factors, including p53, NF-κB, and FOXO1. In vivo, nude mice stably over-expressing PDZK1 had lower tumour weights and volumes and showed significantly down-regulated PTEN phosphorylation in xenograft tumour tissues as compared to the control group. Moreover, low PDZK1 expression strongly correlated with advanced stage and poor prognosis of patients with pancreatic ductal adenocarcinoma. In conclusion, our study elucidated the tumour-suppressor role of PDZK1 in pancreatic cancer through down-regulating PTEN phosphorylation, and established PDZK1 as a potential novel prognostic marker for pancreatic cancer.

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Section: Introductionmentioning

confidence: 99%

PDZ-containing 1 acts as a suppressor of pancreatic cancer by regulating PTEN phosphorylation

Wu³

et al. 2017

Oncotarget

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“…1 Despite in-depth understanding of its pathology and biology, current therapies do not increase the overall survival of pancreatic cancer patients. 2 Profound chemoresistance of pancreatic cancer has been associated with limited benefit to the patients receiving standard chemotherapy. 3 Endoplasmic reticulum (ER) is an organelle, which is mainly involved in the synthesis of protein, modification and folding.…”

Section: Introductionmentioning

confidence: 99%

Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer

et al. 2017

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Pancreatic cancer is one of the most aggressive and difficult to treat cancers. Experimental and clinical evidence suggests that high basal state autophagy in pancreatic tumors could induce resistance to chemotherapy. Recently, we have demonstrated that penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis both in vitro and in vivo; however, the mechanism of autophagy induction by penfluridol was not clear. Several studies have established that endoplasmic reticulum stress could lead to autophagy and inhibit tumor progression. In this study, we demonstrated that penfluridol induced endoplasmic reticulum stress in BxPC-3, AsPC-1, and Panc-1 pancreatic cancer cell lines as indicated by upregulation of endoplasmic reticulum stress markers such as binding protein (BIP), C/EBP homologous protein (CHOP) and inositol requiring 1α (IRE1α) after treatment with penfluridol in a concentration-dependent manner. Inhibiting endoplasmic reticulum stress by pretreatment with pharmacological inhibitors such as sodium phenylbutyrate and mithramycin or by silencing CHOP using CHOP small interfering RNA, blocked penfluridol-induced autophagy. These results clearly indicate that penfluridol-induced endoplasmic reticulum stress lead to autophagy in our model. Western blot analysis of subcutaneously implanted AsPC-1 and BxPC-3 tumors as well as orthotopically implanted Panc-1 tumors demonstrated upregulation of BIP, CHOP, and IRE1α expression in the tumor lysates from penfluridol-treated mice as compared to tumors from control mice. Altogether, our study establishes that penfluridol-induced endoplasmic reticulum stress leads to autophagy resulting in reduced pancreatic tumor growth. Our study opens a new therapeutic target for advanced chemotherapies against pancreatic cancer.

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“…The NGAL has been suggested as a protein playing an important role in carcinogenesis of various neoplasms and a key player in the development of different cancer types [ 10 , 11 ]. In the main part of the analysed dataset NGAL transcripts were significantly higher in most solid tumours compared to the corresponding normal tissues.…”

Section: Discussionmentioning

confidence: 99%

Cystic fluid neutrophil gelatinase-associated lipocalin (NGAL) concentration in differential diagnosis of pancreatic cystic lesions: a new factor enters the scene?

Lipiński

Degowska

Rydzewska

2018

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IntroductionNeutrophil gelatinase-associated lipocalin – 25 kDa peptide – is at present one of the most fascinating and unrecognised proteins implicated in the process of tumour development. Precise assessment of pancreatic cystic lesions is crucial for selecting available treatment options, such as conservative therapy or surgical resection.AimTo determine the utility of NGAL concentration in cyst fluid obtained by endoscopic ultrasound (EUS) with EUS-guided fine-needle aspiration (EUS-FNA) to distinguish neoplastic pancreatic cysts from pseudocysts.Material and methodsTwenty-two patients underwent EUS and FNA of a pancreatic cystic lesion; 9 of these patients underwent surgical resection, providing a histologic diagnosis of the cystic lesion. Furthermore, the final diagnosis was based on cyst fluid cytology, cyst fluid tumour markers (CEA, CA 72-4, CA 19-9), and medical history. Patients were divided in two groups: cystic neoplasms and inflammatory cysts (pseudocysts).ResultsThe final diagnosis was pseudocyst in 7 patients, serous cystadenoma in 4, mucinous cystadenoma in 3, intraductal papillary mucinous neoplasms in 6 patients, and cystic form of pancreatic adenocarcinoma in 2. Cyst fluid analysis of these patients showed that median cyst fluid NGAL for the cystic neoplasm group (211 ng/ml; n = 15) was significantly lower (p = 0.02) than the inflammatory cystic group (4689 ng/ml; n = 7). Correlation analysis showed that only fluid CA 72-4 was positively related to NGAL (r = 0.8, p < 0.01).ConclusionsIn this single-centre study, pancreatic cyst fluid NGAL concentration appeared to be useful in distinguishing neoplastic pancreatic cysts from pseudocysts. Larger studies are recommended to evaluate this role further.

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Adjuvant, neoadjuvant, and experimental regimens in overcoming pancreatic ductal adenocarcinoma

Cited by 8 publications

References 71 publications

PDZ-containing 1 acts as a suppressor of pancreatic cancer by regulating PTEN phosphorylation

PDZ-containing 1 acts as a suppressor of pancreatic cancer by regulating PTEN phosphorylation

Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer

Cystic fluid neutrophil gelatinase-associated lipocalin (NGAL) concentration in differential diagnosis of pancreatic cystic lesions: a new factor enters the scene?

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