Editors' ChoiceCancer

Paradoxical Signaling

Science Signaling  01 Jun 2010:
Vol. 3, Issue 124, pp. ec162
DOI: 10.1126/scisignal.3124ec162

Stimulation of the death receptor CD95 (also known as Fas) on the surface of a cell by its ligand CD95L triggers apoptosis. The abundance of CD95 on tumor cells is often less than that on corresponding nonmalignant cells, and tumor cells can become resistant to apoptosis; however, CD95 is rarely completely absent from tumor cells and some cancer patients have high concentrations of soluble CD95L in the blood. Thus, Chen et al. investigated whether CD95 might play a nonapoptotic role in cancer. Retroviral-mediated expression of short hairpin RNAs (shRNAs) specific for CD95 in a range of cancer cell lines reduced the abundance of CD95 and decreased the sensitivity of these cells to CD95L-induced apoptosis but, surprisingly, also decreased cell proliferation. shRNA-mediated knockdown of CD95L in various cancer cell lines also inhibited cell growth, suggesting an autocrine mechanism of CD95L-CD95 signaling. Injection of mice with an ovarian cancer cell line expressing shRNA specific for CD95 led to the formation of smaller tumors than occurred when mice were injected with cells in which CD95 was not knocked down. Loss of CD95 also reduced the incidence of cancer and the size of tumors in a mouse model of liver cancer. Further experiments implicated c-Jun N-terminal kinase (JNK) in mediating the growth-promoting activity of CD95; however, as Green discusses (see commentary), how CD95 might activate JNK remains unclear. Together, these data implicate CD95 in mediating tumor growth and suggest that antitumor therapies that increase CD95 signaling should be considered.

L. Chen, S.-M. Park, A. V. Tumanov, A. Hau, K. Sawada, C. Feig, J. R. Turner, Y.-X. Fu, I. L. Romero, E. Lengyel, M. E. Peter, CD95 promotes tumour growth. Nature 465, 492–496 (2010). [PubMed]

D. R. Green, A wolf in wolf’s clothing. Nature 465, 433–434 (2010). [PubMed]