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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

Published on: June 7, 2019

Deregulated Akt3 activity promotes development of malignant melanoma

Jill M Stahl1, Arati Sharma, Mitchell Cheung

  • 1Department of Pharmacology, The Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033, USA.

Cancer Research
|October 7, 2004
PubMed

Insights

Selective activation of Akt3 protein promotes melanoma cell survival and tumor development. Targeting Akt3 offers new therapeutic opportunities for advanced melanoma patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • Malignant melanoma is a deadly skin cancer with rising incidence and mortality.
  • Current treatments lack long-term efficacy due to unidentified critical genes and targeted therapies.
  • Akt signaling pathways are implicated in various cancers, but Akt3's specific role in melanoma is unclear.

Purpose of the Study:

  • To identify the specific Akt isoform involved in melanoma progression.
  • To investigate the role of Akt3 in melanoma cell survival and tumor development.
  • To explore Akt3 as a potential therapeutic target for advanced melanoma.

Main Methods:

  • Utilized small interfering RNA (siRNA) to selectively inhibit Akt isoforms (Akt1, Akt2, Akt3) in melanoma cells.
  • Quantified levels of phosphorylated (active) Akt and Akt3 protein during melanoma progression.
  • Analyzed gene copy number for Akt3 and PTEN protein function in melanoma samples.
  • Investigated the effects of Akt3 inhibition (siRNA) and PTEN re-expression on melanoma cell apoptosis and tumor development.

Main Results:

  • Selective inhibition of Akt3, but not Akt1 or Akt2, reduced active Akt levels in melanoma cells, identifying Akt3 as the predominant isoform.
  • Active Akt3 levels progressively increased with melanoma tumor stage, showing highest levels in metastatic melanomas.
  • Akt3 deregulation resulted from gene overexpression and copy number increases, coupled with decreased PTEN function.
  • Akt3 inhibition or PTEN re-expression significantly increased apoptosis, reduced cell survival, and inhibited melanoma tumor development.

Conclusions:

  • Akt3 is a key driver of cell survival and tumor development in a significant portion of nonfamilial melanomas.
  • Akt3 deregulation via overexpression and PTEN loss is common in advanced melanoma.
  • Targeting Akt3 presents a promising therapeutic strategy for advanced-stage melanoma patients.

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