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Dual specificity phosphatases activity on map kinases signaling regulation: impact on pancreatic ductal adenocarcinoma metabolic reprogramming

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with an extremely poor prognosis and overall five-year survival rate of only 5%. This is one of the most intractable cancers and represents the eighth leading cause of cancer-related death in the world. The limited survival rate is mainly due to no screening methods for early diagnosis and tumor invasiveness and metastatic potential, which leads to chemoresistance and thus, few chemotherapeutic options. The highly malignant potential and aggressiveness of PDAC is mainly promoted by oncogenic KRAS activation, which triggers innumerous signaling pathways and thus controls key processes for tumor progression such as cell proliferation, cell survival, metabolism, and oxidative stress control, among others. Additionally, oncogenic KRAS protein has been reported as the main responsible for glycolysis activation and metabolic reprogramming of pancreatic tumor cells. Interestingly, recent studies suggest that the major adjustments in metabolic reprogramming, mediated by KRAS activity, are regulated by MAP kinase activities (MAPKs). MAPKs coordinate several complex signaling networks and their function is precisely regulated by feedback mechanisms mediated by MAP kinase phosphatases. The dual-specificity phosphatases (DUSPs) constitute one of the major classes of phosphatases and have been described in PDAC cells with both oncogenic and tumor suppressor functions. However, the evidences published so far, which describe their role in PDAC, are still highly controversial. Altogether, these considerations lead to the focus of this study: to investigate the dual-specificity phosphatases activity on MAP kinases signaling regulation and their impact on pancreatic ductal adenocarcinoma metabolic reprogramming and tumor progression. Furthermore, a detailed investigation of DUSPs role in MAPKs activation can provide crucial information regarding pancreatic adenocarcinoma biology and improve the knowledge of complex regulatory mechanisms of oncogenic signaling. The new investigation approach proposed by this work could provide important information about tumor biology and enable the discovery of potential diagnostic markers and novel therapeutic targets for the treatment of this highly refractory and lethal disease. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
RUCKERT, MARIANA TANNUS; BROUWERS-VOS, ANNET Z.; NAGANO, LUIS FERNANDO P.; SCHURINGA, JAN JACOB; SILVEIRA, VANESSA SILVA. HUWE1 cooperates with RAS activation to control leukemia cell proliferation and human hematopoietic stem cells differentiation fate. Cancer Gene Therapy, v. 27, n. 10-11 JUL 2020. Web of Science Citations: 0.
RUCKERT, MARIANA TANNUN; DE ANDRADE, PAMELA VIANI; SANTOS, VERENA SILVA; SILVEIRA, VANESSA SILVA. Protein tyrosine phosphatases: promising targets in pancreatic ductal adenocarcinoma. CELLULAR AND MOLECULAR LIFE SCIENCES, v. 76, n. 13, p. 2571-2592, JUL 2019. Web of Science Citations: 1.

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