Oncogenic signaling inhibits c-FLIP expression and promotes cancer cell survival during ECM-detachment

Abstract

Inhibition of programmed cell death pathways is frequently observed in cancer cells where it functions to facilitate tumor progression. However, some proteins involved in the regulation of cell death function dichotomously to both promote and inhibit cell death depending on the cellular context. As such, understanding how cell death proteins are regulated in a context-dependent fashion in cancer cells is of utmost importance. We have uncovered evidence that cellular FLICE-like Inhibitory Protein (c-FLIP), a well-known anti-apoptotic protein, is often downregulated in tumor tissue when compared to adjacent normal tissue. These data argue that c-FLIP may have activity distinct from its canonical role in antagonizing cell death. Interestingly, we have discovered that detachment from extracellular matrix (ECM) serves as a signal to elevate c-FLIP transcription and that oncogenic signaling blocks ECM-detachment-induced c-FLIP elevation. In addition, our data reveal that downregulation of c-FLIP promotes the survival of ECM-detached cells and that c-FLIP overexpression in cancer cells restricts the viability of cancer cells grown in anchorage-independent conditions. Taken together, our study reveals an unexpected role for c-FLIP in constraining the viability of cancer cells during ECM-detachment and raises the idea that c-FLIP may have context-dependent pro- and anti-cell death roles during tumorigenesis.