Overexpression of Akt converts radial growth melanoma to vertical growth melanoma
- Baskaran Govindarajan 1, James E Sligh , Bethaney J Vincent , Meiling Li , Jeffrey A Canter , Brian J Nickoloff , Richard J Rodenburg , Jan A Smeitink , Larry Oberley , Yuping Zhang , Joyce Slingerland , Rebecca S Arnold , J David Lambeth , Cynthia Cohen , Lu Hilenski , Kathy Griendling , Marta Martínez-Diez , José M Cuezva , Jack L Arbiser
- 1Department of Dermatology, Emory University School of Medicine, and Atlanta Veterans Administration Medical Center, Atlanta, Georgia 30322, USA.
- 0Department of Dermatology, Emory University School of Medicine, and Atlanta Veterans Administration Medical Center, Atlanta, Georgia 30322, USA.
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View abstract on PubMed
Summary
This summary is machine-generated.Akt overexpression transforms noninvasive melanoma to invasive melanoma by increasing angiogenesis and reactive oxygen species (ROS). Targeting Akt and ROS may treat advanced melanoma.
Area Of Science
- Oncology
- Molecular Biology
- Cancer Research
Background
- Melanoma incidence is rising, with transformation from radial to vertical growth crucial for metastasis.
- The molecular drivers of melanoma vertical growth remain poorly understood.
- Previous work implicated p42/p44 MAP kinase in radial growth melanoma.
Purpose Of The Study
- To investigate if Akt overexpression is sufficient to drive melanoma transformation from radial to vertical growth.
- To elucidate the molecular mechanisms by which Akt influences melanoma progression.
Main Methods
- Overexpression of Akt in radial growth WM35 melanoma cells.
- Analysis of downstream signaling, including VEGF, reactive oxygen species (ROS) production, and metabolic shifts.
- In vivo subcutaneous tumor implantation assays.
- Investigation of Akt's role in stabilizing cells with mitochondrial DNA mutations and NOX4 expression.
Main Results
- Akt overexpression upregulated VEGF, increased superoxide ROS production, and promoted a shift towards glycolytic metabolism.
- WM35 cells overexpressing Akt formed rapidly growing tumors in vivo, unlike control cells.
- Akt was linked to melanoma transformation via stabilization of cells with mitochondrial DNA mutations and induction of NOX4 expression.
Conclusions
- Akt acts as a molecular switch promoting melanoma angiogenesis and ROS generation, driving aggressive tumor behavior.
- Akt overexpression facilitates melanoma's transition to an invasive phenotype.
- Targeting Akt and ROS presents a potential therapeutic strategy for advanced melanoma.
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