Autophagy in anti-cancer therapy

One cellular program which is important for both cancer cell survival and resistance to therapy is autophagy, a conserved process regulating protein and organelle turnover. It is characterized by the formation of autophagosomes: double membrane- vesicles that fuse with lysosomes where their cargo is degraded. Autophagy is activated as a survival strategy in response to starvation and many types of stress that cancer cells encounter, such as lack of nutrients, acidosis and toxicity induced by anti-cancer therapy. We and others have found that several established anti-cancer drugs, such as DNA-damaging agents and kinase inhibitors, induce autophagy. The impact of an acute autophagy induction on a cell may depend on a stimulus and a cell type [1, 2]. Generally, autophagy is believed to limit the cytotoxic effects of many drugs. In order to identify which of all known anti-cancer drugs that induce autophagy and to evaluate inhibition of autophagy as a therapeutic approach, we have screened a library of all 350 drugs used in anti-cancer treatment and in current clinical trials using an osteosarcoma model system: HOS cells stably transfected with GFP-LC3, and found 104 drugs to modulate autophagy. The goal is to evaluate the potential of a synergy between the anti-cancer drugs and inhibition of autophagy. Here, both genetic and pharmacological inhibition of autophagy is used, at either initiation stage of autophagic process or by blocking autophagic flux using lysosomal inhibitors. Novel Vps34 inhibitors that have been developed by Sprint Bioscience are used in these studies in cancer cell lines of different origin, including breast cancer. Both 2D and 3D model systems are used as well as evaluation of synergy between drugs in mouse models.

In some cancer cells, autophagy may instead promote cell death induced by anti-cancer therapy. We previously found that glucocorticoid (GC) dexamethasone (Dex), a key drug in the treatment of lymphoid malignancies, induced profound autophagy that contributed to the death of ALL cells [3]. Interestingly, we found Dex to profoundly affect leukemic cell energy metabolism by inhibiting glucose uptake and utilization [4]. However, data suggest that inhibition of glucose metabolism per se will not activate autophagy in these cells. We are currently investigating the mechanisms of autophagy induction by GCs with specific focus on metabolic pathways modulated by Dex in leukemic cells using metabolome and proteome approach. We also investigate metabolic features of leukemic cells that might be responsible for the resistance to treatment. 

Collaborations

  • The Childhood Cancer Research Unit, Department of Women and Child Health, Astrid Lindgren Children’s Hospital.
  • CBCS - Chemical Biology Consortium, KI and SciLife
  • K. Wennerberg, FIMM, Finland.
  • Sprint Bioscience, NOVUM, Huddinge
  • The COST European autophagy network.
  • R. Nilsson and C. Wheelock, CMM, KI
  • J. Lehtiö, OnkPat, KI and  SciLife

Sprint Bioscience

References

1. Autophagy as the main means of cytotoxicity by glucocorticoids in hematological malignancies.
Grandér D, Kharaziha P, Laane E, Pokrovskaja K, Panaretakis T
Autophagy 2009 Nov;5(8):1198-200

2. Autophagy: cancer therapy's friend or foe?
Grandér D, Panaretakis T
Future Med Chem 2010 Feb;2(2):285-97

3. Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy.
Laane E, Tamm K, Buentke E, Ito K, Kharaziha P, Khahariza P, et al
Cell Death Differ. 2009 Jul;16(7):1018-29

4. Glucocorticoid-induced cell death is mediated through reduced glucose metabolism in lymphoid leukemia cells.
Buentke E, Nordström A, Lin H, Björklund A, Laane E, Harada M, et al
Blood Cancer J 2011 Jul;1(7):e31

Cancer and OncologyCell Biology