Deregulated Akt3 activity promotes development of malignant melanoma

Jill M. Stahl, Arati Sharma, Mitchell Cheung, Melissa Zimmerman, Jin Q. Cheng, Marcus W. Bosenberg, Mark Kester, Lakshman Sandirasegarane, Gavin P. Robertson

Research output: Contribution to journalArticle

424 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7002-7010
Number of pages9
JournalCancer Research
Volume64
Issue number19
DOIs
StatePublished - Oct 1 2004

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Melanoma
PTEN Phosphohydrolase
Small Interfering RNA
Cell Survival
Haploinsufficiency
Neoplasms
Gene Dosage
Skin Neoplasms
Genes
Protein Isoforms
Therapeutics
Apoptosis
Neoplasm Metastasis
Mortality
Incidence
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Stahl, Jill M. ; Sharma, Arati ; Cheung, Mitchell ; Zimmerman, Melissa ; Cheng, Jin Q. ; Bosenberg, Marcus W. ; Kester, Mark ; Sandirasegarane, Lakshman ; Robertson, Gavin P. / Deregulated Akt3 activity promotes development of malignant melanoma. In: Cancer Research. 2004 ; Vol. 64, No. 19. pp. 7002-7010.
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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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Stahl, JM, Sharma, A, Cheung, M, Zimmerman, M, Cheng, JQ, Bosenberg, MW, Kester, M, Sandirasegarane, L & Robertson, GP 2004, 'Deregulated Akt3 activity promotes development of malignant melanoma', Cancer Research, vol. 64, no. 19, pp. 7002-7010. https://doi.org/10.1158/0008-5472.CAN-04-1399

Deregulated Akt3 activity promotes development of malignant melanoma. / Stahl, Jill M.; Sharma, Arati; Cheung, Mitchell; Zimmerman, Melissa; Cheng, Jin Q.; Bosenberg, Marcus W.; Kester, Mark; Sandirasegarane, Lakshman; Robertson, Gavin P.

In: Cancer Research, Vol. 64, No. 19, 01.10.2004, p. 7002-7010.

Research output: Contribution to journalArticle

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AU - Stahl, Jill M.

AU - Sharma, Arati

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AU - Zimmerman, Melissa

AU - Cheng, Jin Q.

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AU - Kester, Mark

AU - Sandirasegarane, Lakshman

AU - Robertson, Gavin P.

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AB - 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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Stahl JM, Sharma A, Cheung M, Zimmerman M, Cheng JQ, Bosenberg MW et al. Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Research. 2004 Oct 1;64(19):7002-7010. https://doi.org/10.1158/0008-5472.CAN-04-1399