Mitochondrial dysfunction in DDR-related cancer predisposition syndromes.

Given the key role of mitochondria in various cellular events, it is not surprising that mitochondrial dysfunction (MDF) is seen in many pathological conditions, in particular cancer. The mechanisms defining MDF are not clearly understood and may involve genetic defects, misbalance of reactive oxygen species (ROS), impaired autophagy (mitophagy), acquired mutations in mitochondrial or nuclear DNA and inability of cells to cope with the consequences. The importance of MDF arises from its detection in the syndromes with defective DNA damage response (DDR) and cancer predisposition. Here, we will focus on the dual role of these syndromes in cancer predisposition and MDF with specific emphasis on impaired autophagy.

Identification of metabolic changes leading to cancer susceptibility in Fanconi anemia cells.

Fanconi anemia (FA) is a chromosomal instability disorder of bone marrow associated with aplastic anemia, congenital abnormalities and a high risk of malignancies. The identification of more than two dozen FA genes has revealed a plethora of interacting proteins that are mainly involved in repair of DNA interstrand crosslinks (ICLs). Other important findings associated with FA are inflammation, oxidative stress response, mitochondrial dysfunction and mitophagy. In this work, we performed quantitative proteomic and metabolomic analyses on defective FA cells and identified a number of metabolic abnormalities associated with cancer. In particular, an increased de novo purine biosynthesis, a high concentration of fumarate, and an accumulation of purinosomal clusters were found. This was in parallel with decreased OXPHOS and altered glycolysis. On the whole, our results indicate an association between the need for nitrogenous bases upon impaired DDR in FA cells with a subsequent increase in purine metabolism and a potential role in oncogenesis.

DNA damage response and resistance of cancer stem cells.

The cancer stem cell (CSC) model defines tumors as hierarchically organized entities, containing a small population of tumorigenic CSC, or tumour-initiating cells, placed at the apex of this hierarchy. These cells may share common qualities with chemo- and radio-resistant cancer cells and contribute to self-renewal activities resulting in tumour formation, maintenance, growth and metastasis. Yet, it remains obscure what self-defense mechanisms are utilized by these cells against the chemotherapeutic drugs or radiotherapy. Recently, attention has been focused on the pivotal role of the DNA damage response (DDR) in tumorigenesis. In line with this note, an increased DDR that prevents CSC and chemoresistant cells from genotoxic pressure of chemotherapeutic drugs or radiation may be responsible for cancer metastasis. In this review, we focus on the current knowledge concerning the role of DDR in CSC and resistant cancer cells and describe the existing opportunities of re-sensitizing such cells to modulate therapeutic treatment effects.

Reactive Oxygen Species-Mediated Autophagy Defines the Fate of Cancer Stem Cells.

Significance: A fraction of tumorigenic cells, also known as tumor initiating or cancer stem cells (CSCs), is thought to drive tumor growth, metastasis, and chemoresistance. However, little is known regarding mechanisms that convey relevant pathways contributing to their self-renewal, proliferation, and differentiation abilities. Recent Advances: Recent works on CSCs provide evidence on the role of redox disruption and regulation of autophagic flux. This has been linked to increased DNA repair capacity and chemoresistance. Critical Issues: The current review summarizes the most recent studies assessing the role of redox homeostasis, autophagy, and chemoresistance in CSCs, including some novel findings on microRNAs and their role in horizontal transfer within cancer cell populations. Future Directions: Rational anticancer therapy and prevention should rely on the fact that cancer is a redox disease with the CSCs being the apex modulated by redox-mediated autophagy. Antioxid. Redox Signal. 28, 1066-1079.

Targeting cancer cells through antibiotics-induced mitochondrial dysfunction requires autophagy inhibition.

A significant part of current research studies utilizes various cellular models which imply specific antibiotics-containing media as well as antibiotics used for clonal selection or promoter de/activation. With the great success of developing such tools, mitochondria, once originated from bacteria, can be effectively targeted by antibiotics. For that reason, some studies propose antibiotics-targeting of mitochondria as part of anticancer therapy. Here, we have focused on the effects of various classes of antibiotics on mitochondria in cancer and non-cancer cells and demonlow mitochondrial membrane potential, reduced ATP production, altered morphology and lowered respiration rate which altogether suggested mitochondrial dysfunction (MDF). This was in parallel with increased level of reactive oxygen species (ROS) and decreased activity of mitochondrial respiration complexes. However, both survival and repopulation capacity of cancer cells was not significantly affected by the antibiotics, perhaps due to a glycolytic shift or activated autophagy. In turn, simultaneous inhibition of autophagy and treatment with antibiotics largely reduced tumorigenic properties of cancer cells suggesting potential strategy for anticancer therapy.