The role of CD95 and CD95 ligand in cancer

Abstract

CD95 (Fas/APO-1) and its ligand, CD95L, have long been viewed as a death receptor/death ligand system that mediates apoptosis induction to maintain immune homeostasis. In addition, these molecules are important in the immune elimination of virus-infected cells and cancer cells. CD95L was, therefore, considered to be useful for cancer therapy. However, major side effects have precluded its systemic use. During the last 10 years, it has been recognized that CD95 and CD95L have multiple cancer-relevant nonapoptotic and tumor-promoting activities. CD95 and CD95L were discovered to be critical survival factors for cancer cells, and were found to protect and promote cancer stem cells. We now discuss five different ways in which inhibiting or eliminating CD95L, rather than augmenting, may be beneficial for cancer therapy alone or in combination with standard chemotherapy or immune therapy.

Genetic disruption of oncogenic Kras sensitizes lung cancer cells to Fas receptor-mediated apoptosis

“…However, normal somatic cells also express Fas receptor. For example, hepatocytes are highly sensitive to FAS-mediated apoptosis; the systemic injection of high-dose Jo2 antibody induces apoptosis in the liver (28). Thus, FAS-activating antibody needs to be specifically delivered to tumor cells to avoid liver damage.…”

“…4A). As reported before, binding of Fas ligand or Fas-activating antibodies to Fas receptor triggers apoptosis through cell-intrinsic pathway (28). We tested whether a Fas-activating antibody can induce Fas-mediated cell death in Kras −/− cells.…”

“…This analysis indicated that these candidates may have a putative role in development or progression of human lung cancer. Moreover, some of these of the candidates, such as DLC1 (36), FAT4 (37), and FAS (28), are well-known tumor suppressors.…”

“…Among the top 10 genes highly expressed in Kras −/− cells from the RNA-seq, we focused to investigate Fas (which encodes the Fas receptor) for two reasons. First, the Fas receptor triggers apoptosis through cellintrinsic pathway (38,39), and it has been implicated in various malignancies (28), hence an attractive therapeutic target. Second, based on previous work (26,27), Fas expression has been shown to be regulated by Ras-dependent pathways.…”

Alive failures behind the windows of cancer therapy

“…In some studies, on failed apoptosis, TRAILR signaling was reported to lead Capasee-dependent cleavage of RHO-associated protein kinase 1 (ROCK1), activating RHO GTPase and causing membrane blebbing and cell migration (Somasekharan et al 2013). Moreover, various non-apoptotic, pro-oncogenic functions were described in FAS signaling, including stimulation of proliferation and migration (Peter et al 2015). However, not only proproliferatives effects, FAS signaling can also exert pro-survival functions.…”