Dynamic interplay between autophagic flux and Akt during melanoma progression in vitro

Abstract

Despite advances in cancer diagnosis and therapy, metastatic melanoma remains untreatable, due to its notorious resistance to apoptosis, deeming traditional therapies obsolete. Deregulated PI3K/Akt signalling is a common oncogenic event enabling melanocyte transformation and represents a significant and 'druggable' pathway in melanoma. Emerging data show that the ability of cancer cells to survive is also facilitated by alteration of vital homoeostatic mechanisms, such as autophagy. Although the role of autophagy in melanoma is still controversial, recent studies suggest that basal autophagy is down-modulated in primary melanomas. However, the dynamic connection between pro-tumorigenic PI3K/Akt and autophagy during melanoma progression has not been systematically studied. By using human primary melanocytes, incipient melanoma and metastatic melanoma cell lines, we show that early in melanomagenesis, increased Akt activity is associated with a low baseline autophagic flux. However, during melanoma progression, metastatic melanoma cells regain the ability to stimulate autophagic flux, supporting survival. Heightened autophagy is associated with an attenuated Akt activation status and can be suppressed by overexpressing a constitutive active mutant of Akt. On the other hand, blocking the higher Akt activity of primary melanoma is sufficient to incite autophagy. Interestingly, we found that although Akt supports survival of melanocytes and all melanoma cell lines, autophagy inhibition specifically targeted the metastatic melanoma cells, thus indicating a stage-specific requirement for Akt and autophagic flux, throughout melanoma progression. Therefore, this study highlights a dynamic interplay between Akt signalling and autophagic rescue in melanoma, which should be considered in the design of therapeutic strategies targeting these pathways.