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Therapeutic Implications of Targeting AKT Signaling in Melanoma.

Madhunapantula SV, Robertson GP - Enzyme Res (2011)

Bottom Line: Accumulating preclinical evidence demonstrates that therapeutic agents targeting these kinases alone or in combination with other pathway members could be effective for the long-term treatment of advanced-stage disease.However, currently, no selective and effective therapeutic agent targeting these kinases has been identified for clinical use.Finally, key issues that remain to be answered and future directions for interested researchers pertaining to this signaling cascade are highlighted.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.

ABSTRACT
Identification of key enzymes regulating melanoma progression and drug resistance has the potential to lead to the development of novel, more effective targeted agents for inhibiting this deadly form of skin cancer. The Akt3, also known as protein kinase B gamma, pathway enzymes regulate diverse cellular processes including proliferation, survival, and invasion thereby promoting the development of melanoma. Accumulating preclinical evidence demonstrates that therapeutic agents targeting these kinases alone or in combination with other pathway members could be effective for the long-term treatment of advanced-stage disease. However, currently, no selective and effective therapeutic agent targeting these kinases has been identified for clinical use. This paper provides an overview of the key enzymes of the PI3K pathway with emphasis placed on Akt3 and the negative regulator of this kinase called PTEN (phosphatase and tensin homolog deleted on chromosome 10). Mechanisms regulating these enzymes, their substrates and therapeutic implications of targeting these proteins to treat melanoma are also discussed. Finally, key issues that remain to be answered and future directions for interested researchers pertaining to this signaling cascade are highlighted.

No MeSH data available.


Related in: MedlinePlus

Cotargeting Akt3 and V600EB-Raf inhibits melanoma cell proliferation in vitro.  Two hundred picomoles of siRNA targeting Akt3 and increasing (3, 6, and 12 picomoles) amounts of siRNA inhibiting V600EB-Raf were introduced alone or in combination into UACC 903 melanoma cell line by Amaxa transfection and effect on anchorage independent growth ability measured using MTS assay.  The data shows a dose-dependent inhibition of cell viability when Akt3 and V600EB-Raf were inhibited.  However, maximal effect was observed only when Akt3 and V600EB-Raf targeted together, indicating the necessity of inhibiting multiple signaling cascades    [46, 151].
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fig9: Cotargeting Akt3 and V600EB-Raf inhibits melanoma cell proliferation in vitro. Two hundred picomoles of siRNA targeting Akt3 and increasing (3, 6, and 12 picomoles) amounts of siRNA inhibiting V600EB-Raf were introduced alone or in combination into UACC 903 melanoma cell line by Amaxa transfection and effect on anchorage independent growth ability measured using MTS assay. The data shows a dose-dependent inhibition of cell viability when Akt3 and V600EB-Raf were inhibited. However, maximal effect was observed only when Akt3 and V600EB-Raf targeted together, indicating the necessity of inhibiting multiple signaling cascades [46, 151].

Mentions: Several lines of evidence now suggest that it might be required to target multiple signaling pathways to inhibit melanoma development. For example, a recent study shows that inhibiting V600EB-Raf using PLX-4720 induced resistance to apoptosis by activating Akt signaling [48, 149]. Furthermore, it is also now well established that targeting V600EB-Raf not only induces resistance to various therapeutic agents but also stimulates the activity of C-Raf and wt B-Raf signaling thereby triggering the formation of keratoacanthomas and basal cell carcinomas [7, 184]. Therefore, it is important to target multiple signaling cascades to inhibit melanoma development. However, it is not completely known which targets should be inhibited. Studies have provided some directions in this regard by showing synergistically acting melanoma tumor inhibition by simultaneously targeting PI3K/Akt3 and MAP kinase signaling pathways [32, 46, 151, 185–187]. For example (a) delivering siRNAs inhibiting Akt3 and V600EB-Raf synergistically inhibited melanoma tumor cells growth in culture or in xenografted melanoma tumors [46, 151] (Figures 9 and 10); (b) combining nanoliposomal ceramide with sorafenib synergistically reduced melanoma cell growth [188]; (c) pharmacological agents inhibiting MAPK (U0126, PD98059 and PD325901) and mTORC1 (using rapamycin) more effectively reduced melanoma cells growth compared to either of the agents tested singly [24, 189, 190]; (d) topical application of LY-294002 and U0126 in combination effectively decreased melanoma tumor incidence in the transgenic TPRas mouse model when compared to either of these agents alone [191]; (e) targeting PI3K and mTOR using dual inhibitors NVP-BBD130 and NVP-BEZ235 effectively reduced the size of primary melanoma tumors and inhibited cervical lymph node metastasis in a syngenic mouse melanoma model. Although these studies demonstrate the potential therapeutic efficacy of combined target inhibition, no complete tumor reduction occurred in any of these studies, warranting the identification of other candidates and target combinations for treating this disease.


Therapeutic Implications of Targeting AKT Signaling in Melanoma.

Madhunapantula SV, Robertson GP - Enzyme Res (2011)

Cotargeting Akt3 and V600EB-Raf inhibits melanoma cell proliferation in vitro.  Two hundred picomoles of siRNA targeting Akt3 and increasing (3, 6, and 12 picomoles) amounts of siRNA inhibiting V600EB-Raf were introduced alone or in combination into UACC 903 melanoma cell line by Amaxa transfection and effect on anchorage independent growth ability measured using MTS assay.  The data shows a dose-dependent inhibition of cell viability when Akt3 and V600EB-Raf were inhibited.  However, maximal effect was observed only when Akt3 and V600EB-Raf targeted together, indicating the necessity of inhibiting multiple signaling cascades    [46, 151].
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3065045&req=5

fig9: Cotargeting Akt3 and V600EB-Raf inhibits melanoma cell proliferation in vitro. Two hundred picomoles of siRNA targeting Akt3 and increasing (3, 6, and 12 picomoles) amounts of siRNA inhibiting V600EB-Raf were introduced alone or in combination into UACC 903 melanoma cell line by Amaxa transfection and effect on anchorage independent growth ability measured using MTS assay. The data shows a dose-dependent inhibition of cell viability when Akt3 and V600EB-Raf were inhibited. However, maximal effect was observed only when Akt3 and V600EB-Raf targeted together, indicating the necessity of inhibiting multiple signaling cascades [46, 151].
Mentions: Several lines of evidence now suggest that it might be required to target multiple signaling pathways to inhibit melanoma development. For example, a recent study shows that inhibiting V600EB-Raf using PLX-4720 induced resistance to apoptosis by activating Akt signaling [48, 149]. Furthermore, it is also now well established that targeting V600EB-Raf not only induces resistance to various therapeutic agents but also stimulates the activity of C-Raf and wt B-Raf signaling thereby triggering the formation of keratoacanthomas and basal cell carcinomas [7, 184]. Therefore, it is important to target multiple signaling cascades to inhibit melanoma development. However, it is not completely known which targets should be inhibited. Studies have provided some directions in this regard by showing synergistically acting melanoma tumor inhibition by simultaneously targeting PI3K/Akt3 and MAP kinase signaling pathways [32, 46, 151, 185–187]. For example (a) delivering siRNAs inhibiting Akt3 and V600EB-Raf synergistically inhibited melanoma tumor cells growth in culture or in xenografted melanoma tumors [46, 151] (Figures 9 and 10); (b) combining nanoliposomal ceramide with sorafenib synergistically reduced melanoma cell growth [188]; (c) pharmacological agents inhibiting MAPK (U0126, PD98059 and PD325901) and mTORC1 (using rapamycin) more effectively reduced melanoma cells growth compared to either of the agents tested singly [24, 189, 190]; (d) topical application of LY-294002 and U0126 in combination effectively decreased melanoma tumor incidence in the transgenic TPRas mouse model when compared to either of these agents alone [191]; (e) targeting PI3K and mTOR using dual inhibitors NVP-BBD130 and NVP-BEZ235 effectively reduced the size of primary melanoma tumors and inhibited cervical lymph node metastasis in a syngenic mouse melanoma model. Although these studies demonstrate the potential therapeutic efficacy of combined target inhibition, no complete tumor reduction occurred in any of these studies, warranting the identification of other candidates and target combinations for treating this disease.

Bottom Line: Accumulating preclinical evidence demonstrates that therapeutic agents targeting these kinases alone or in combination with other pathway members could be effective for the long-term treatment of advanced-stage disease.However, currently, no selective and effective therapeutic agent targeting these kinases has been identified for clinical use.Finally, key issues that remain to be answered and future directions for interested researchers pertaining to this signaling cascade are highlighted.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.

ABSTRACT
Identification of key enzymes regulating melanoma progression and drug resistance has the potential to lead to the development of novel, more effective targeted agents for inhibiting this deadly form of skin cancer. The Akt3, also known as protein kinase B gamma, pathway enzymes regulate diverse cellular processes including proliferation, survival, and invasion thereby promoting the development of melanoma. Accumulating preclinical evidence demonstrates that therapeutic agents targeting these kinases alone or in combination with other pathway members could be effective for the long-term treatment of advanced-stage disease. However, currently, no selective and effective therapeutic agent targeting these kinases has been identified for clinical use. This paper provides an overview of the key enzymes of the PI3K pathway with emphasis placed on Akt3 and the negative regulator of this kinase called PTEN (phosphatase and tensin homolog deleted on chromosome 10). Mechanisms regulating these enzymes, their substrates and therapeutic implications of targeting these proteins to treat melanoma are also discussed. Finally, key issues that remain to be answered and future directions for interested researchers pertaining to this signaling cascade are highlighted.

No MeSH data available.


Related in: MedlinePlus