The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.
Deregulated Akt3 Activity Promotes Development of Malignant Melanoma
Abstract
Malignant melanoma is the skin cancer with the most significant impact on man, carrying the highest risk of death from metastasis. Both incidence and mortality rates continue to rise each year, with no effective long-term treatment on the horizon. In part, this reflects lack of identification of critical genes involved and specific therapies targeted to correct these defects. We report that selective activation of the Akt3 protein promotes cell survival and tumor development in 43 to 60% of nonfamilial melanomas. The predominant Akt isoform active in melanomas was identified by showing that small interfering RNA (siRNA) against only Akt3, and not Akt1 or Akt2, lowered the amount of phosphorylated (active) Akt in melanoma cells. The amount of active Akt3 increased progressively during melanoma tumor progression with highest levels present in advanced-stage metastatic melanomas. Mechanisms of Akt3 deregulation occurred through a combination of overexpression of Akt3 accompanying copy number increases of the gene and decreased PTEN protein function occurring through loss or haploinsufficiency of the PTEN gene. Targeted reduction of Akt3 activity with siRNA or by expressing active PTEN protein stimulated apoptotic signaling, which reduced cell survival by increasing apoptosis rates thereby inhibiting melanoma tumor development. Identifying Akt3 as a selective target in melanoma cells provides new therapeutic opportunities for patients in the advanced stages of this disease.
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Cites
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The protein kinase B/Akt signalling pathway in human malignancy
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Growth retardation and increased apoptosis in mice with homozygous disruption of the akt1 gene
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Molecular alterations of the AKT 2 oncogene in ovarian and breast carcinomas
Bellacosa, A., De Feo, D., Godwin, A. K., Bell, D. W., Cheng, J. Q., Altomare, D. A., Wan, M., Dubeau, L., Scambia, G., Masciullo, V., et al. (1995) · International Journal of Cancer · doi:10.1002/ijc.2910640412 · Cited by 837
Self-citationPeng, X.-D., Xu, P.-Z., Chen, M.-L., Hahn-Windgassen, A., Skeen, J., Jacobs, J., Sundararajan, D., Chen, W. S., Crawford, S. E., Coleman, K. G., et al. (2003) · Genes & Development · doi:10.1101/gad.1089403 · Cited by 826
Apoptosis and melanoma chemoresistance
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Cited by
Melanoma biology and new targeted therapy
Gray-Schopfer, V., Wellbrock, C., & Marais, R. (2007) · Nature · doi:10.1038/nature05661 · Cited by 1,371
PI3K/AKT signaling pathway and cancer: An updated review
Martini, M., De Santis, M. C., Braccini, L., Gulluni, F., & Hirsch, E. (2014) · Annals of Medicine · doi:10.3109/07853890.2014.912836 · Cited by 1,020
The mTOR Signalling Pathway in Human Cancer
Pópulo, H., Lopes, J. M., & Soares, P. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms13021886 · Cited by 830
Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway
Polivka, J., & Janku, F. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.12.004 · Cited by 765
Melanoma: from mutations to medicine
Tsao, H., Chin, L., Garraway, L. A., & Fisher, D. E. (2012) · Genes & Development · doi:10.1101/gad.191999.112 · Cited by 496
Metadata
- Authors
- Stahl, J. M., Sharma, A., Cheung, M., Zimmerman, M., Cheng, J. Q., Bosenberg, M. W., Kester, M., Sandirasegarane, L., & Robertson, G. P.
- Venue
- Cancer Research
- Published
- 2004-10-01
- Volume
- 64
- Issue
- 19
- Pages
- 7002-7010
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2161724145
- Cited by
- 594
- References
- 32
- FWCI
- 9.29
- Type
- journal article
- Language
- en
- Open access
- closed
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- Stahl, J. M., Sharma, A., Cheung, M., Zimmerman, M., Cheng, J. Q., Bosenberg, M. W., Kester, M., Sandirasegarane, L., & Robertson, G. P. (2004). Deregulated Akt3 Activity Promotes Development of Malignant Melanoma. Cancer Research. https://doi.org/10.1158/0008-5472.can-04-1399
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