Felipe Muñoz

The Mitochondrial Complex(I)ty of Cancer

Recent evidence highlights that the cancer cell energy requirements vary greatly from normal cells and that cancer cells exhibit different metabolic phenotypes with variable participation of both glycolysis and oxidative phosphorylation. NADH–ubiquinone oxidoreductase (Complex I) is the largest complex of the mitochondrial electron transport chain and contributes about 40% of the proton motive force required for mitochondrial ATP synthesis. In addition, Complex I plays an essential role in biosynthesis and redox control during proliferation, resistance to cell death, and metastasis of cancer cells. Although knowledge about the structure and assembly of Complex I is increasing, information about the role of Complex I subunits in tumorigenesis is scarce and contradictory. Several small molecule inhibitors of Complex I have been described as selective anticancer agents; however, pharmacologic and genetic interventions on Complex I have also shown pro-tumorigenic actions, involving different cellular signaling. Here, we discuss the role of Complex I in tumorigenesis, focusing on the specific participation of Complex I subunits in proliferation and metastasis of cancer cells.

Services Commitments in the Pacific Alliance

The Pacific Alliance was established to deepen the integration process among its members by speeding up measures for enabling the free circulation of goods and financial flows, the delivery of services and the movement of people across borders. Services have become one of the main work packages of the Alliance, as they are seen as an alternative means for member countries to achieve higher economic growth and development. High expectations characterize the level of ambition and commitments in trade in services. Therefore, this chapter will analyze the services dimension of the Pacific Alliance. A review of the commitments made by PA members in their services negotiations is made, noticing that the Alliance does not seems to represent a big step towards services openness.

FR58P1a; a new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1/AMPK/β1-integrin pathway

Highly malignant triple-negative breast cancer (TNBC) cells rely mostly on glycolysis to maintain cellular homeostasis; however, mitochondria are still required for migration and metastasis. Taking advantage of the metabolic flexibility of TNBC MDA-MB-231 cells to generate subpopulations with glycolytic or oxidative phenotypes, we screened phenolic compounds containing an ortho-carbonyl group with mitochondrial activity and identified a bromoalkyl-ester of hydroquinone named FR58P1a, as a mitochondrial metabolism-affecting compound that uncouples OXPHOS through a protonophoric mechanism. In contrast to well-known protonophore uncoupler FCCP, FR58P1a does not depolarize the plasma membrane and its effect on the mitochondrial membrane potential and bioenergetics is moderate suggesting a mild uncoupling of OXPHOS. FR58P1a activates AMPK in a Sirt1-dependent fashion. Although the activation of Sirt1/AMPK axis by FR58P1a has a cyto-protective role, selectively inhibits fibronectin-dependent adhesion and migration in TNBC cells but not in non-tumoral MCF10A cells by decreasing β1-integrin at the cell surface. Prolonged exposure to FR58P1a triggers a metabolic reprograming in TNBC cells characterized by down-regulation of OXPHOS-related genes that promote cell survival but comprise their ability to migrate. Taken together, our results show that TNBC cell migration is susceptible to mitochondrial alterations induced by small molecules as FR58P1a, which may have therapeutic implications.

Trade in Services and Development: The Case of Perception in Chile

Trade in services and its positive relation with countries’ development has been a consideration in the design of public policies. In particular, since the return of democracy, it has been pointed out by Chilean authorities the intention to improve services exports to add value and diversify its basket. Since the first decade of the 2000 the State has implemented a series of programs and strategies directed to achieve these objectives. However, the matrix remains anchored in natural resources, particularly copper. Although trade in services has increased, it has not done so as expected. In order to understand the reasons why public policies intend to promote the service sector have failed achieving their objective, this work has interviewed experts from the public, private and academic sector, international organizations and NGOs to collect their perception on policies to promote services exports implemented in the period 1990 – 2014. For a better understanding of the results, three overlapping levels are distinguished, in a logical hierarchy from greater to lesser extent: Level I: Considerations on economic doctrines and corporate cultures. Level II: Considerations on the specificity of service industry and economic considerations. Level III: Considerations on specific policies and instruments. Some conclusions and recommendations are presented at the end.