The mitochondrial master regulator gene PGC1alpha in novel sporadic melanoma cell lines: correlations with BRAF mutational status
Journal of Translational Medicine volume 12, Article number: P9 (2014)
Metabolic reprogramming is commonly found in cancer but it is poorly understood in melanoma. Recent works [1, 2] provided new insights concerning molecular mechanisms involved in mitochondrial biogenesis of melanoma. This work aims to find possible correlations between pathways involved in the onset and progression of the disease in order to provide supporting information in this field. In particular we studied the behaviour of the mitochondrial master regulator gene PGC1alpha in novel sporadic melanoma cell lines and its relations with BRAF mutational status.
Materials and methods
We studied new cell lines extracted from sporadic metastatic melanomas (hmel1, M3, Mba72) and primary melanomas (hmel9, hmel11), genotyped for genes involved in melanoma development compared to control melanoma cell lines (HBL, LND1) wt for MC1R and BRAF genes. Hmel1, hmel9 and hmel11 have already been described in Zanna et al., 2011  and Zanna et al., 2013 . We evaluated PGC1α levels and some of its mitochondrial target genes and the mitochondrial respiratory capacity, the amount of ROS, and the lactate level. We related these data to BRAF mutational stauts and analyzed MITF and cAMP levels.
The HBL and LND1 cell lines, wt for BRAF, highly express PGC1alpha while hmel1, hmel9, hmel11, Mba72, M3, presenting BRAF mutations at the V600 residue, show a downregulation of this gene. MITF expression levels were more abundant in HBL and LND1 cell lines with respect to the other cell lines harbouring BRAF mutations. There is a direct correspondence between PGC1alpha and MITF levels: higher levels of PGC1alpha are associated with an enhanced MITF quantity. The analysis of cAMP levels in our melanoma cell lines showed a similar trend, being higher in wt BRAF cell lines compared to the other cell lines.
Our data confirm the key role of BRAF mutations, MITF and cAMP levels in melanoma biology, suggesting a very important association with the transcriptional co-activator PGC1alpha, involved in energy metabolism and in mitochondrial biogenesis but also in various physiological stimuli that are reprogrammed in melanoma cells. These data support the divergent pathways hypothesis for melanoma, which may require a reappraisal of targeted cancer prevention and target therapeutic activities.
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Vasquez F, Lim J-H, Chim H, Bhalia K, Girnun G, Pierce K, Clish CB, Granter SR, Widlund HR, Spiegelman BM, Puigserver P: PGC1a Expression Defines a Subset of Human Melanoma Tumors with Increased Mitochondrial Capacity and Resistance to Oxidative Stress. Cancer Cell. 2013, 23 (3): 287-301. 10.1016/j.ccr.2012.11.020.
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Zanna P, Maida I, Grieco C, Guida S, Turbin Sevilla MC, De Summa S, Tommasi S, Vena GA, Filotico R, Guida G: Three novel human sporadic melanoma cell lines: signaling pathways controlled by MC1R, BRAF and ßcatenin. J Biol Regul Homeost Agents. 2013, 27 (1): 131-141.
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Guida, G., Maida, I., Ferretta, A. et al. The mitochondrial master regulator gene PGC1alpha in novel sporadic melanoma cell lines: correlations with BRAF mutational status. J Transl Med 12 (Suppl 1), P9 (2014). https://doi.org/10.1186/1479-5876-12-S1-P9