Implication of PI3K/Akt pathway in pancreatic cancer: When PI3K isoforms matter?

Baer, Romain; Cintas, Celia; Therville, Nicole; Guillermet-Guibert, Julie

doi:10.1016/j.jbior.2015.05.001

Cited by 74 publications

(61 citation statements)

References 121 publications

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“…2A). The activation of mTORCI is a key feature of many PDACs that results in increased protein translation, stem cell renewal, proliferation, and inhibition of autophagy via ULK1 kinase activation 94,95 .…”

Section: Deregulated Signaling Network In Pancreatic Cancermentioning

confidence: 99%

Molecular Pathogenesis of Pancreatic Cancer

Grant

Hua

Singh

2016

Progress in Molecular Biology and Translational Science

143

133

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Pancreatic cancers arise predominantly from ductal epithelial cells of the exocrine pancreas and are of the ductal adenocarcinoma histological subtype (PDAC). PDAC is an aggressive disease associated with a poor clinical prognosis, weakly effective therapeutic options, and a lack of early detection methods. Furthermore, the genetic and phenotypic heterogeneity of PDAC complicates efforts to identify universally efficacious therapies. PDACs commonly harbor activating mutations in the KRAS oncogene, which is a potent driver of tumor initiation and maintenance. Inactivating mutations in tumor suppressor genes such as CDKN2A/p16, TP53 and SMAD4 cooperate with KRAS mutations to cause aggressive PDAC tumor growth. PDAC can be classified into 3-4 molecular subtypes by global gene expression profiling. These subtypes can be distinguished by distinct molecular and phenotypic characteristics. This chapter will provide an overview of the current knowledge of PDAC pathogenesis at the genetic and molecular level as well as novel therapeutic opportunities to treat this highly aggressive disease.

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Section: Deregulated Signaling Network In Pancreatic Cancermentioning

confidence: 99%

Molecular Pathogenesis of Pancreatic Cancer

Grant

Hua

Singh

2016

Progress in Molecular Biology and Translational Science

143

133

View full text Add to dashboard Cite

show abstract

“…Class I PI3Ks generate lipids (PI(3,4,5)P3) that modulate the activity of a range of signaling proteins, including protein kinases (such as Akt/PKB). The regulatory subunit p85α of PI3K and Akt2 isoforms are confirmed to be overexpressed in human pancreatic adenocarcinomas 19. The PI3K/Akt/mTOR pathway plays a key role in numerous cellular processes, including metabolism, cell survival, differentiation, proliferation, motility, and angiogenesis 20.…”

Section: Introductionmentioning

confidence: 99%

A blockade of PD-L1 produced antitumor and antimetastatic effects in an orthotopic mouse pancreatic cancer model via the PI3K/AkT/MTOR signaling pathway

Zhao

Li²,

Liu³

et al. 2017

OTT

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BackgroundPancreatic cancer is one of the most aggressive and intractable malignant tumors, and most deaths from pancreatic cancer are related to metastases. It has been demonstrated in vitro that overexpression of programmed death-ligand 1 (PD-L1) correlates with a lack of phosphatase and tensin homologue (PTEN) expression in pancreatic cancer tissue. This loss of PTEN expression may aberrantly activate the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, and thereby promote tumor cell survival, proliferation, and disease progression. In this study, we investigated the potential therapeutic effect of blockading PD-L1 expression on the progression of pancreatic cancer and its spontaneous liver metastases in vivo by inhibiting the PI3K/Akt/mTOR signaling pathway.MethodsWe investigated the effect of blockading PD-L1 in an orthotopic pancreatic cancer mouse model. The pancreatic tumor weights and inhibition ratios were determined after treatment with antimouse PD-L1 antibody for 5 weeks. We used immunohistochemistry methods to investigate PD-L1 expression in pancreatic cancer tissue and spontaneous liver metastasis tissue. The levels of mRNA and protein expression for various components involved in the PI3K/Akt/mTOR signaling pathway as well as for matrix metalloproteinases-2 and -9 (MMP2 and MMP9) were measured by reverse transcription polymerase chain reaction (RT-PCR) and Western blot methods, respectively.ResultsBlockading PD-L1 significantly inhibited tumor growth and decreased the levels of PD-L1 expression in tumor tissue. Furthermore, the levels of PTEN mRNA and protein expression were elevated, while the levels of phospho-Akt (p-Akt) and phospho-mTOR (p-mTOR) protein were decreased in pancreatic cancer and liver metastasis tissues after establishing a PD-L1 blockade. In addition, a PD-L1 blockade decreased the levels of MMP2 and MMP9 mRNA and protein expression in tumor tissues.ConclusionOur results suggest that a blockade of PD-L1 may inhibit the growth and metastasis of pancreatic cancer by modulating the PI3K/Akt/mTOR pathway.

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“…Activating KRAS mutations occur early, followed by loss of p16 , and then later, inactivation of TP53 and SMAD4 [3, 4]; however, targeting these events has proven to be very difficult. Conversely, the phosphatidylinositol-3 kinase (PI3K)/Akt downstream pathway represents an exciting new target for therapeutic intervention, especially because it emerged among the core signaling pathways in PDAC [5, 6], and several known inhibitors are currently in clinical trials (www.clinicaltrials.gov). …”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, it failed the phase III clinical trials for treatment of colon cancer and relapsed refractory multiple myeloma (www.clinicaltrials.gov). These failures, together with the disappointing response rates to perifosine as a single agent in most solid tumors, including PDAC, prompt further studies into its mechanism of action [6] as well as on synergistic combinations.…”

Section: Introductionmentioning

confidence: 99%

Phospho-Akt overexpression is prognostic and can be used to tailor the synergistic interaction of Akt inhibitors with gemcitabine in pancreatic cancer

et al. 2017

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BackgroundThere is increasing evidence of a constitutive activation of Akt in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and chemoresistance. Therefore, we evaluated the expression of phospho-Akt in PDAC tissues and cells, and investigated molecular mechanisms influencing the therapeutic potential of Akt inhibition in combination with gemcitabine.MethodsPhospho-Akt expression was evaluated by immunohistochemistry in tissue microarrays (TMAs) with specimens tissue from radically-resected patients (n = 100). Data were analyzed by Fisher and log-rank test. In vitro studies were performed in 14 PDAC cells, including seven primary cultures, characterized for their Akt1 mRNA and phospho-Akt/Akt levels by quantitative-RT-PCR and immunocytochemistry. Growth inhibitory effects of Akt inhibitors and gemcitabine were evaluated by SRB assay, whereas modulation of Akt and phospho-Akt was investigated by Western blotting and ELISA. Cell cycle perturbation, apoptosis-induction, and anti-migratory behaviors were studied by flow cytometry, AnnexinV, membrane potential, and migration assay, while pharmacological interaction with gemcitabine was determined with combination index (CI) method.ResultsImmunohistochemistry of TMAs revealed a correlation between phospho-Akt expression and worse outcome, particularly in patients with the highest phospho-Akt levels, who had significantly shorter overall and progression-free-survival. Similar expression levels were detected in LPC028 primary cells, while LPC006 were characterized by low phospho-Akt. Remarkably, Akt inhibitors reduced cancer cell growth in monolayers and spheroids and synergistically enhanced the antiproliferative activity of gemcitabine in LPC028, while this combination was antagonistic in LPC006 cells. The synergistic effect was paralleled by a reduced expression of ribonucleotide reductase, potentially facilitating gemcitabine cytotoxicity. Inhibition of Akt decreased cell migration and invasion, which was additionally reduced by the combination with gemcitabine. This combination significantly increased apoptosis, associated with induction of caspase-3/6/8/9, PARP and BAD, and inhibition of Bcl-2 and NF-kB in LPC028, but not in LPC006 cells. However, targeting the key glucose transporter Glut1 resulted in similar apoptosis induction in LPC006 cells.ConclusionsThese data support the analysis of phospho-Akt expression as both a prognostic and a predictive biomarker, for the rational development of new combination therapies targeting the Akt pathway in PDAC. Finally, inhibition of Glut1 might overcome resistance to these therapies and warrants further studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0371-1) contains supplementary material, which is available to authorized users.

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Implication of PI3K/Akt pathway in pancreatic cancer: When PI3K isoforms matter?

Cited by 74 publications

References 121 publications

Molecular Pathogenesis of Pancreatic Cancer

Molecular Pathogenesis of Pancreatic Cancer

A blockade of PD-L1 produced antitumor and antimetastatic effects in an orthotopic mouse pancreatic cancer model via the PI3K/AkT/MTOR signaling pathway

Phospho-Akt overexpression is prognostic and can be used to tailor the synergistic interaction of Akt inhibitors with gemcitabine in pancreatic cancer

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