Projects: Unit of Toxicology

Molecular Mechanisms of Cell Death

The main goal of this project is to expand our knowledge of the molecular mechanisms of various cell death modalities and the importance of defective cell death execution in the resistance of tumor cells to treatment. The information emerging from this study will help us understand the multiple roles of dysregulation of cell death in cancer pathogenesis.

Specific aims of this study are:

  1. To investigate caspase-2 function and mechanisms of activation.
  2. To analyze mitochondrial function during cell death.
  3. To evaluate the importance of crosstalk between autophagy and apoptosis for the sensitivity of lung cancer cells to treatment.

Financing

Vetenskapsrådet

Contact

Professor, senior

Boris Zhivotovsky

Organizational unit: Toxicology
E-mail: Boris.Zhivotovsky@ki.se

Apoptotic signaling pathways regulated by miRNA in non-small cell lung cancer cells: roadmap for therapies

The main goal of this project is to understand how miRNA-regulated pathways influence the response of non-small cell lung cancer cells to therapy. The information emerging from this study may have direct relevance in discovering specific targets for successful treatment of this type of lung cancer.

Specific aims of this study are:

  1. To identify the role of Tudor staphylococcal nuclease (Tudor-SN) in sensitivity/resistance of NSCLC cells to chemotherapy.
  2. To recognize the role of miR-214 in regulation of cell death and carcinogenesis.
  3. To undertake an attempt to investigate expression of Tudor-SN and miR-214 in biopsies obtained from patients with NSCLC.

Financing
Cancerfonden

Contact

Professor, senior

Boris Zhivotovsky

Organizational unit: Toxicology
E-mail: Boris.Zhivotovsky@ki.se

Targeting energy producing pathways as a promising strategy in neuroblastoma therapy

The main goal of this project is obtaining new data on the mechanisms of neuroblastoma (NB) cell elimination using as a target cellular energy producing pathways, in particular connected to mitochondria, and validation of our findings in an in vivo model. Targeting cellular energy metabolism using various modulators of glycolysis, glutaminolysis, or oxidative phosphorylation represents a promising strategy to sensitize tumor cells to treatment with chemotherapeutic drugs and eliminate them. The information emerging from the proposed study will help us to understand how tumor cells can be specifically committed to die, without harming non-malignant tissues and will be beneficial for improving NB treatment regimes.

Specific aims of this study are:

  1. Investigation of glutamine addiction as a new therapeutic target in neuroblastoma treatment.
  2. Investigation of involvement of glutaminase in outer mitochondrial membrane permeabilization in NB cells with different status of the MycN oncogene.
  3. In vivo validation of the results obtained in vitro using NB mouse models.

Financing
Barncancerfonden

Contact

Professor, senior

Boris Zhivotovsky

Organizational unit: Toxicology
E-mail: Boris.Zhivotovsky@ki.se

Cross-talk between autophagy and apoptosis in sensitivity/resistance of lung cancer cells to treatment

The main goal of this study is to explore the contribution of autophagy to the formation/accumulation of free radicals in cancer cells and to establish how the effect of autophagy modulation on free radical formation might affect apoptotic death of lung adenocarcinoma cells. Successful development of the project will permit us to take an attempt to sensitize this tumor entity to therapy by modulating the level of apoptosis/autophagy.

The specific aims of the project can be summarized as follows:

  1. By knocking down the specific autophagy-related gene products to identify the molecular mechanisms involving in free radical formation.
  2. To understand whether the alterations in free radical formation/accumulation caused by modulation of autophagy could be involved in different cell death outcome.
  3. To analyze and correlate the level of intrinsic autophagy in paraffin-embedded samples obtained from patients carrying adenocarcinoma with their response to treatment.

Financing
Cancerföreningen

Contact

Professor, senior

Boris Zhivotovsky

Organizational unit: Toxicology
E-mail: Boris.Zhivotovsky@ki.se