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. 2019 Jun 20;116(28):13943–13951. doi: 10.1073/pnas.1903297116

Fig. 5.

Fig. 5.

Cartoon representation of the proposed mechanism of GST P1-1–mediated resistance to cis-DDP. (Left, a) In nonstressed cells, in the presence of basal expression levels of GST P1-1, the monomeric (or dimeric enzyme) is complexed with GSH and JNK, maintaining low JNK activity and thus inhibiting apoptotic cell death. (Left, b) Following cis-DDP treatment and intracellular activation, Pt ions coordinate to 2 or more subunits of GST P1-1 through the cysteine residues. (Left, c) GST P1-1 oligomerization-induced JNK release and its subsequent activation via phosphorylation leads to apoptotic cell death. (Right) In cells characterized by GST P1-1 overexpression and higher GSH content (i.e., cancer cells), the GST P1-1 monomers and dimers are complexed with JNK (d), and upon cis-DDP treatment (e), the released Pt ions are both sequestered by GST P1-1 and spontaneously conjugated to GSH (GS-Pt). However, the GST P1-1 expression levels are so high (f) that only a small amount of GST P1-1 dissociates from JNK, which is insufficient to activate the apoptotic signaling cascade.