Mitochondrial cholesterol makes response to chemotherapy difficult in hepatic cancer
Cancer is a disease characterized by important metabolic alterations. Not only these adaptative changes give higher proliferative capacity to cancer cells, but they also contribute to higher resistance to chemotherapeutic agents. The research group led by Dr. José Carlos Fernández-Checa in the Institut d’Investigacions Biomèdiques de Barcelona of the CSIC (IIBB-CSIC), a centre linked to the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), is centred in the mitochondrion and its role in programmed cell death or apoptosis. The mitochondrion is the organelle in charge of the cell’s respiration and of energy generation to satisfy important metabolic functions, which are altered in cancer. In an article published in Cancer Research with Joan Montero and Albert Morales as first signatories an Ana Colell as co-director of the study, IIBB-CSIC-IDIBAPS researchers describe how the increase of cholesterol in the mitochondrial membrane plays a key role in the resistance to cytotoxic agents acting via mitochondrion, including doxorubicin, a common drug in chemotherapy. This research has been developed in the framework of the Centre of Network Biomedical Research on Hepatic and Digestive diseases (CIBERehd).
Hepatocarcinoma is the most frequent form of hepatic cancer. It has a high mortality rate due to, among other causes, the lack of an effective treatment and due to its high resistance against the current chemotherapy strategy. In order to improve the quality of treatments, it is important to identify the strategies permitting the cell to avoid chemotherapy’s toxicity. The supraphysiological level of mitochondrial cholesterol in hepatocarcinoma and in other cancers is well known, but its role in the mitochondrial regulation of cellular death and resistance to chemotherapy was not known. Cholesterol is an indispensable molecule for the cell membrane, and normally, its endogenous synthesis is closely regulated to prevent the accumulation of cholesterol, precisely what occurs in carcinogenesis.
After the application of several strategies in hepatocarcinoma samples, such as the inhibition of the de novo cholesterol synthesis and its mitochondrial transport, researchers concluded that cholesterol increase in the mitochondrial membrane was responsible for chemotherapy resistance. In collaboration with the University of the Basque Country and the Swiss firm Merk Serono International, a model in liposomes simulating the composition of the mitochondrial membrane was developed in order to check the effects of cholesterol on its fluidity and response to several stimuli. The mitochondrion contains indispensable molecules so that the cell initiates apoptosis, vut it is necessary that pores are formed in the membrane in order to release these molecules into the cell and then initiate cell death mechanisms. This process requires an appropriate fluidity environment to permit permeabilisation of the mitochondrial membrane and the release of the mitochondrial proapoptotic molecules. Results point to mitochondrial cholesterol as the main responsible of the disorders in the mitochondrial membrane fluidity as the factors avoiding a satisfactory response to treatment.
Statins and squalene synthase inhibitors, such as YM-53601 inhibit cholesterol formation and, therefore, its availability to be integrated in the mitochondrial membrane. Statins are commonly used drugs in the treatment of cardiovascular treatments, and its use has shown surprising effects in the incidence of certain types of cancer (e.g. colorectal or melanoma). Results of this research work could throw new light to new therapeutic strategies with the combination of statins and chemotherapeutic agents for a better treatment of liver cancer.