Northwestern University Feinberg School of Medicine

Peter Lab

DICE - a novel concept for cancer therapy

The Peter lab previously showed that CD95 promotes growth of cancer cells (1). More recently they found that elimination of CD95 or CD95L results in a form of cell death that is independent of caspase-8, RIPK1/MLKL, and p53, is not inhibited by Bcl-xL expression, and preferentially affects cancer cells. All tumors that formed in mouse models of low-grade serous ovarian cancer or chemically induced liver cancer with tissue specific deletion of CD95 still expressed CD95, suggesting that cancer cannot form in the absence of CD95. Death induced by CD95R/L elimination (DICE) is characterized by an increase in cell size, production of mitochondrial ROS, and DNA damage. It resembles a necrotic form of mitotic catastrophe. No single drug was found to completely block this form of cell death, and it could also not be blocked by the knockdown of a single gene, making it a promising new way to kill cancer cells. Most recently, the Peterlab found that stimulation of CD95 on cancer cells or reducing miR-200c levels increases the number of cancer stem cells (CSCs), which are more sensitive to induction of DICE than non-CSC, while becoming less sensitive to CD95 mediated apoptosis (3). In contrast, induction of DICE or overexpression of miR-200c reduces the number of cancer stem cells. This data is consistent with a previousobservation that overexpression of miR-200c sensitizes cancer cells to canonical CD95-mediated apoptosis (4).  Killing of cancer cells can be maximized by concomitant induction of DICE and CD95-mediated apoptosis, which eliminates both CSCs and non-CSCs, respectively.

diceThe physiological function of DICE, a hypothesis.
It is clear that cells of the immune system employ well established activities of CD95/CD95L in the elimination of neoplastically transformed cells. Infiltrating immune cells kill cancer cells by activating the canonical caspase-8 dependent apoptosis pathway in the cancer cells (Figure step I). On rare occasions, this process fails due to mutations or epigenetic deregulation of genes in the cancer cells rendering them resistant to CD95 mediated apoptosis. Accumulating data suggest that under these conditions stimulation of CD95 on the tumor cells by CD95L drives tumor growth, motility, and dedifferentiation of the cancer cells (Figure step II). When tumor cells delete the CD95 genes or mutate CD95, DICE is turned on (Figure step III). DICE may, therefore, be a fail-safe mechanism that prevents the survival of cells that are devoid of CD95 and, hence, cannot be eliminated by the immune system through CD95L/CD95-mediated apoptosis (5). The Peterlab is currently testing whether induction of DICE can be achieved in vivo to treat cancer by using siRNAs coupled to gold nanoparticles.

References

  1. Chen, L., Park, S.M., Tumanov, A., Hau, A., Sawada, K., Feig, C., Turner, J., Fu, Y.X., Romeo, I., Lengyel, E. and Peter, M.E. (2010) CD95 promotes tumour growth. Nature, 465, 492-496.
  2. Hadji, H., Ceppi, P., Murmann, A.E., Brockway, S., A., Pattanayak, A., Bhinder, B., Hau, H., De Chant, S., Parimi, V., Kolesza, P., Richards, J., Chandel, N., Djaballah, H. and Peter, M.E. (2014) Death Induced by CD95 or CD95 Ligand Elimination. Cell Reports, 5, 208-222.
  3. Ceppi, P., Hadji, A., Kohlhapp, F., Hau, A., Murmann, A.E. and Peter, M.E. (2014) CD95 and CD95L promote and protect cancer stem cells. Nature Commun. 5:5238.
  4. Schickel, R, Park, S.-P., Murmann, A.E. and Peter, M.E. (2010) miR-200 regulates induction of apoptosis through CD95 by targeting FAP-1. Mol. Cell. 38, 908-915.
  5. Peter, M.E. (2014) DICE: A novel tumor surveillance mechanism - a new therapy for cancer? Cell Cycle, 13, 1373-1378.