Thioredoxin interacting protein (Txnip) acts as a tumor suppressor and is a critical regulator of energy metabolism. Txnip is an α-arrestin protein and comprises conserved PPxY motifs known to interact with WW domains. Txnip bound to in vitro-translated WW domain containing proteins, including TAZ and NEDD family of E3 ubiquitin ligases including NEDD4, NEDD4L, ITCH, WWP2, Smurf1 and Smurf2. Using blue native PAGE (BNPAGE), we showed that Txnip is involved in the formation of high molecular weight complexes (250 and 1,000 to 1,300 kDa) in DU145 prostatic cancer cells. Treatment with the proteasome inhibitor bortezomib increased the accumulation of Txnip in these high molecular weight complexes, while treatment with glucose or metabolic regulator metformin altered the accumulation pattern. These results suggest that Txnip containing high order protein complexes are metabolically regulated through proteasomal degradation.