Vav1 Down-Modulates Akt2 Expression in Cells from Pancreatic Ductal Adenocarcinoma: Nuclear Vav1 as a Potential Regulator of Akt Related Malignancy in Pancreatic Cancer.

Silvia Grassilli,Simonetta Buglioni,Federica Brugnoli,Rossano Lattanzio,Valeria Bertagnolo

doi:10.3390/biomedicines8100379

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive tumor malignancy worldwide, mainly due to uncontrolled metastasis. Among the numerous molecules deregulated in PDAC, different members of the Akt pathways are of great importance because they are involved in tumor cell proliferation, migration, and invasion. We have recently demonstrated that Vav1, ectopically expressed in solid tumors, is capable of down-modulating expression and/or activation of specific Akt isoforms in breast cancer cells. By using pancreatic cell lines expressing different basal levels of Vav1, we demonstrated here that Vav1 down-regulates the expression of Akt2, known to correlate with tumor metastases and resistance to therapy. In particular, while the silencing of Vav1 is sufficient to induce Akt2, its up-modulation reduces Akt2 levels only when Vav1 accumulates inside the nucleus of PDAC cells. Moreover, in PDAC tissues, we revealed that high nuclear levels of Vav1 correlate with low Akt2 expression. Although we cannot demonstrate the mechanisms involved, our results provide new insights into the role of Vav1 in PDAC and, as targeting specific members of the Akt family is a promising therapeutic chance in solid tumors, they suggest that Vav1, by down-modulating Akt2, has potential as a molecular target in PDAC.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors, characterized by aggressive growth, which leads to a 5-year overall survival of less than 6%, without substantial progress in the last few years [1,2]
Among the role played by the Akt isoforms in tumors, Akt1 is generally correlated with cell proliferation, survival, and apoptosis, while Akt2, which has become one of the most studied targets in diverse solid tumors, is mainly associated with cell migration and metastasis [20,21,22]
A peculiar modulation of the Akt family was recently shown in cells from invasive breast tumors with different phenotypes [13] and involved Vav1, a multidomain protein physiologically expressed in hematopoietic cells and whose ectopic expression in non-hematopoietic tissues was generally associated with the appearance of a tumor phenotype [24]

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors, characterized by aggressive growth, which leads to a 5-year overall survival of less than 6%, without substantial progress in the last few years [1,2]. The increased activation of the PI3K/Akt pathway is common in PDAC and has been associated with higher histological tumor grade and worse prognosis [3,4,5]. Both Akt and Akt are markedly activated in primary pancreatic tumors and tumor metastases, and Akt was positively correlated with resistance of PDAC to chemotherapy [6]. Vav is ectopically expressed in a number of non-hematopoietic cancers, including PDAC [9], in which this protein seems to be involved in signal transduction processes correlated with aggressive tumor phenotypes [10,11,12]. PDAC patients with Vav1-positive tumors have a worse prognosis compared to patients with Vav1-negative tumors [10,12], and the ability of

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