Anoikis Resistance: An Essential Prerequisite for Tumor Metastasis

Figure 1

Schematic representation of intrinsic and exrtinsic pathways of anoikis. When cells are detached from ECM, normal cells induce anoikis through both intrinsic and exrtinsic pathways. Upon cell detachment, FAS and FasL are upregulated and FLIP is downregulated, leading to activation of Caspase 8, followed by activation of caspase-7 and caspase-3. Loss of cell adhesion also increases and activates proapoptotic Bcl-2 proteins (Bik, Puma, Bad, Noxa, Bmf, Bid, Bim, Bax, and Bak), which inactivate antiapoptotic Bcl-2 proteins (Bcl-2, Bcl-xL, Mcl-1), and thus causing mitochondria membrane permeabilization through Bax/Bak oligomerization. Released cytochrome c from mitochondria activates caspase-9, subsequently caspase-3. Smac/DIABLO is released and inhibits XIAP, an inhibitor of apoptosis, leading to caspase-3 activation. Activaiton of these pathways leads to anoikis. However, increased FLIP expression in cancer cells inhibits extrinsic pathway and oncogene expression such as EGFR and hypoxia downregulate Bmf and Bim, resulting in inhibition of mitochondrial pathway in suspended cells. Accordingly, cancer cells acquire anoikis resistance.