An Integrated Meta-Analysis of Secretome and Proteome Identify Potential Biomarkers of Pancreatic Ductal Adenocarcinoma

Oliveira, Grasieli de; Freire, Paula Paccielli; Cury, Sarah Santiloni; Moraes, Diogo de; Oliveira, Jakeline Santos; Dal-Pai-Silva, Maeli; Reis, Patrícia P.; Carvalho, Robson Francisco

doi:10.3390/cancers12030716

Cited by 21 publications

(18 citation statements)

References 185 publications

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“…Other mechanisms of DDP-induced cytotoxicity are involved in impairing glycolysis, mitochondrial dysfunction, and accumulation of reactive oxygen species (ROS) [ 9 ]. However, DDP exhibits severe side-effects that can lead to discontinuation of therapy and acquired drug resistance, which may contribute to the treatment failure in pancreatic cancer [ 10 ]. Currently, the depletion of glutathione caused by DDP and the inactivation of glutathione peroxidase were found to play a vital role in its underlying mechanism [ 11 , 12 ], suggesting that combination chemotherapy based on ferroptosis could be developed to strengthen the therapeutic effect and reduce the cytotoxicity of DDP.…”

Section: Introductionmentioning

confidence: 99%

DHA exhibits synergistic therapeutic efficacy with cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via modulation of iron metabolism

Wang

et al. 2021

Cell Death Dis

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Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal cancer with limited treatment options. Cisplatin (DDP) is used as a mainstay of chemotherapeutic agents in combination with other drugs or radiotherapy for PDAC therapy. However, DDP exhibits severe side-effects that can lead to discontinuation of therapy, and the acquired drug resistance of tumor cells presents serious clinical obstacles. Therefore, it is imperative to develop a more effective and less toxic therapeutic strategy. We and others have previously discovered that dihydroartemisinin (DHA) represents a safe and promising therapeutic agent to preferentially induce cancer cell ferroptosis. In the present study, we find that DHA could intensively strengthen the cytotoxicity of DDP and significantly reduce its effective concentrations both in vitro and in vivo. Combination of DHA and DDP synergistically inhibits the proliferation and induces DNA damage of PDAC cells. Mechanically, the combinative treatment impairs mitochondrial homeostasis, characterized by destroyed mitochondrial morphology, decreased respiratory capacity, reduced ATP production, and accumulated mitochondria-derived ROS. Further studies show that ferroptosis contributes to the cytotoxic effects in PDAC cells under the challenge of DHA and DDP, together with catastrophic accumulation of free iron and unrestricted lipid peroxidation. Moreover, pharmacologic depleting of the free iron reservoir or reconstituted expression of FTH contributes to the tolerance of DHA/DDP-induced ferroptosis, while iron addition accelerates the ferroptotic cell death. In summary, these results provide experimental evidence that DHA acts synergistically with DDP and renders PDAC cells vulnerable to ferroptosis, which may act as a promising therapeutic strategy.

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Section: Introductionmentioning

confidence: 99%

DHA exhibits synergistic therapeutic efficacy with cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via modulation of iron metabolism

Wang

et al. 2021

Cell Death Dis

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“…A recent meta-analysis combined publicly available proteome and secretome data with the aim of identifying biomarkers of PC. While this analysis did not identify any protein that was shared by all of the 55 included secretome and proteome studies, by selecting proteins found in 2 or more studies an intersection between the two exposed 43 proteins common between proteome and secretome analyses [ 100 ]. Notably, 31 genes related to these secretome-proteins were shown to be upregulated in PC samples obtained from TCGA compared to control samples, while 39 such genes were revealed to be predictors of worse overall survival in PC [ 100 ].…”

Section: Identification Of Biomarkers In Pcls and Pc Using Omicsmentioning

confidence: 99%

Multi-Omic Biomarkers as Potential Tools for the Characterisation of Pancreatic Cystic Lesions and Cancer: Innovative Patient Data Integration

Kane

Mellotte

Conlon

et al. 2021

Cancers

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Pancreatic cancer (PC) is among the most aggressive types of cancer, having caused over 495,000 deaths worldwide in 2020, with increasing annual incidence. Pancreatic cystic lesions (PCLs) are protrusions found within or on the surface of the pancreas, and in many cases have the potential to become malignant. Current methods of characterising PCLs are imperfect and there is a profound need for improved diagnostic algorithms. This review highlights the importance of biological markers in the context of PCLs and PC, with a focus on ‘omics’-related work. Successful integration of different ‘omics’ data could aid in the identification of a novel integrated biomarker profile for the risk stratification of patients with PCLs and PC.

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“…TPI catalyzes the interconversion of dihydroxyacetone phosphate (DHP) into G3P. TPI is highly expressed in several cancer types [ 158 , 159 , 160 ], including PDA [ 13 ], and plays a role in migration and invasion of tumor cells [ 9 , 13 , 38 , 161 ]. Meta-analysis has shown that TPI was increased in the proteomes and secretomes of PDA patients [ 38 ].…”

Section: Triose Phosphate Isomerase (Tpi) and Glyceraldehyde-3-phomentioning

confidence: 99%

“…TPI is highly expressed in several cancer types [ 158 , 159 , 160 ], including PDA [ 13 ], and plays a role in migration and invasion of tumor cells [ 9 , 13 , 38 , 161 ]. Meta-analysis has shown that TPI was increased in the proteomes and secretomes of PDA patients [ 38 ]. Proteomic analysis of PDA patient sera treated with GEM revealed that TPI serum levels were higher in patients with the worst prognoses, suggesting TPI as a putative prognostic marker of response to GEM treatment [ 13 , 39 ].…”

Section: Triose Phosphate Isomerase (Tpi) and Glyceraldehyde-3-phomentioning

confidence: 99%

The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

et al. 2021

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Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer, characterized by unrestrained progression, invasiveness and treatment resistance. To date, there are limited curative options, with surgical resection as the only effective strategy, hence the urgent need to discover novel therapies. A platform of onco-immunology targets is represented by molecules that play a role in the reprogrammed cellular metabolism as one hallmark of cancer. Due to the hypoxic tumor microenvironment (TME), PDA cells display an altered glucose metabolism—resulting in its increased uptake—and a higher glycolytic rate, which leads to lactate accumulation and them acting as fuel for cancer cells. The consequent acidification of the TME results in immunosuppression, which impairs the antitumor immunity. This review analyzes the genetic background and the emerging glycolytic enzymes that are involved in tumor progression, development and metastasis, and how this represents feasible therapeutic targets to counteract PDA. In particular, as the overexpressed or mutated glycolytic enzymes stimulate both humoral and cellular immune responses, we will discuss their possible exploitation as immunological targets in anti-PDA therapeutic strategies.

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An Integrated Meta-Analysis of Secretome and Proteome Identify Potential Biomarkers of Pancreatic Ductal Adenocarcinoma

Abstract: Pancreatic ductal adenocarcinoma (

Cited by 21 publications

References 185 publications

DHA exhibits synergistic therapeutic efficacy with cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via modulation of iron metabolism

DHA exhibits synergistic therapeutic efficacy with cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via modulation of iron metabolism

Multi-Omic Biomarkers as Potential Tools for the Characterisation of Pancreatic Cystic Lesions and Cancer: Innovative Patient Data Integration

The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

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