Emerging therapeutics for targeting Akt in cancer

Basu, Alakananda

doi:10.2741/4419

Cited by 12 publications

(6 citation statements)

References 52 publications

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“…However, recent work suggests that there are important isoform-specific functional differences [13, 21–23]. Our data suggests that Akt1 is the main isoform responsible for ovarian cancer cell proliferation and protection against apoptosis and other studies have demonstrated an important role for Akt1 in ovarian cancer cell viability [24].…”

Section: Discussionsupporting

confidence: 46%

Akt isoform specific effects in ovarian cancer progression

et al. 2016

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Ovarian cancer remains a significant therapeutic problem and novel, effective therapies are needed. Akt is a serine-threonine kinase that is overexpressed in numerous cancers, including ovarian. Mammalian cells express three Akt isoforms which are encoded by distinct genes. Although there are several Akt inhibitors in clinical trials, most indiscriminately target all isoforms. Current in vitro data and animal knockout experiments suggest that the Akt isoforms may have divergent roles. In this paper, we determined the isoform-specific functions of Akt in ovarian cancer cell proliferation in vitro and in ovarian cancer progression in vivo. For in vitro experiments, murine and human ovarian cancer cells were treated with Akt inhibitors and cell viability was assessed. We used two different in vivo approaches to identify the roles of Akt isoforms in ovarian cancer progression and their influence on the primary tumor and tumor microenvironment. In one experiment, wild-type C57Bl6 mice were orthotopically injected with ID8 cells with stable knockdown of Akt isoforms. In a separate experiment, mice null for Akt 1-3 were orthotopically injected with WT ID8 cells (Figure 1). Our data show that inhibition of Akt1 significantly reduced ovarian cancer cell proliferation and inhibited tumor progression in vivo. Conversely, disruption of Akt2 increased tumor growth. Inhibition of Akt3 had an intermediate phenotype, but also increased growth of ovarian cancer cells. These data suggest that there is minimal redundancy between the Akt isoforms in ovarian cancer progression. These findings have important implications in the design of Akt inhibitors for the effective treatment of ovarian cancer.

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Section: Discussionsupporting

confidence: 46%

Akt isoform specific effects in ovarian cancer progression

et al. 2016

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“…Finally, the efforts to dissect the molecular mechanisms of AKT isoform-specific signaling will provide new insights for designing more effective and selective therapeutics for cancer treatment2354555657. In this regard, isoform-specific siRNA, microRNAs, inhibitors and antibodies constitute tools to elucidate the relative contributions of each AKT isoform signal and localization to cancer spreading.…”

Section: Discussionmentioning

confidence: 99%

AKT1 and AKT2 isoforms play distinct roles during breast cancer progression through the regulation of specific downstream proteins

Riggio

Perrone

Polo

et al. 2017

Sci Rep

108

110

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The purpose of this study was to elucidate the mechanisms associated with the specific effects of AKT1 and AKT2 isoforms in breast cancer progression. We modulated the abundance of specific AKT isoforms in IBH-6 and T47D human breast cancer cell lines and showed that AKT1 promoted cell proliferation, through S6 and cyclin D1 upregulation, but it inhibited cell migration and invasion through β1-integrin and focal adhesion kinase (FAK) downregulation. In contrast, AKT2 promoted cell migration and invasion through F-actin and vimentin induction. Thus, while overexpression of AKT1 promoted local tumor growth, downregulation of AKT1 or overexpression of AKT2 promoted peritumoral invasion and lung metastasis. Furthermore, we evaluated The Cancer Genome Atlas (TCGA) dataset for invasive breast carcinomas and found that increased AKT2 but not AKT1 mRNA levels correlated with a worse clinical outcome. We conclude that AKT isoforms play specific roles in different steps of breast cancer progression, with AKT1 involved in the local tumor growth and AKT2 involved in the distant tumor dissemination, having AKT2 a poorer prognostic value and consequently being a worthwhile target for therapy.

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“…The PI3K /AKT pathway can be activated in tumor cells by a number of mechanisms. AKT serine/threonine kinase plays a crucial role in the regulation of cell growth, proliferation, and survival 10 . The kinases in the AKT family, are composed of three members, AKT1, AKT2, and AKT3.…”

Section: Introductionmentioning

confidence: 99%

Metformin Inhibits Tumorigenesis and Tumor Growth of Breast Cancer Cells by Upregulating miR-200c but Downregulating AKT2 Expression

Zhang

Yuan

et al. 2017

J. Cancer

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Background: Metformin has been reported to inhibit the growth of various types of cancers, including breast cancer. Yet the mechanisms underlying the anticancer effects of metformin are not fully understood. Growing evidence suggests that metformin's anticancer effects are mediated at least in part by modulating microRNAs, including miR-200c, which has a tumor suppressive role in breast cancer. We hypothesized that miR-200c has a role in the antitumorigenic effects of metformin on breast cancer cells.Methods: To delineate the role of miR-200c in the effects of metformin on breast cancer, plasmids containing pre-miR-200c or miR-200c inhibitor were transfected into breast cancer cell lines. The MDA-MB-231, BT549, MCF-7, and T-47-D cells' proliferation, apoptosis, migration, and invasion were assessed. The antitumor role of metformin in vivo was investigated in a MDA-MB-231 xenograft tumor model in SCID mice.Results: Metformin significantly inhibited the growth, migration, and invasion of breast cancer cells, and induced their apoptosis; these effects were dependent on both dose and time. Metformin also suppressed MDA-MB-231 tumor growth in SCID mice in vivo. Metformin treatment was associated with increased miR-200c expression and decreased c-Myc and AKT2 protein expression in both breast cancer cells and tumor tissues. Overexpression of miR-200c exhibited effects on breast cancer cells similar to those of metformin treatment. In contrast, inhibiting the expression of miR-200c increased the growth, migration, and invasion of MCF-7 and MDA-MB-231 cells.Conclusion: Metformin inhibits the growth and invasiveness of breast cancer cells by upregulation of miR-200c expression by targeting AKT2. These findings provide novel insight into the molecular functions of metformin that suggest its potential as an anticancer agent.

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Emerging therapeutics for targeting Akt in cancer

Cited by 12 publications

References 52 publications

Akt isoform specific effects in ovarian cancer progression

Akt isoform specific effects in ovarian cancer progression

AKT1 and AKT2 isoforms play distinct roles during breast cancer progression through the regulation of specific downstream proteins

Metformin Inhibits Tumorigenesis and Tumor Growth of Breast Cancer Cells by Upregulating miR-200c but Downregulating AKT2 Expression

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