Can be Hikeshi a Potential Target for Hyperthermic Therapy?

: While hyperthermia (HT) is a promising modality for cancer therapy, major difficulty with the use of HT is the development of thermotolerance due to the elevation of heat shock proteins (HSPs), which function as molecular chaperons. Among the HSPs, Hsp70 possesses cytoprotective activity and plays a critical role in the acquisition of thermotolerance. Upon heat stress, Hsp70 rapidly translocates from the cytoplasm to nucleus. Recently, the protein Hikeshi, also known as the gene product of C11orf73, has been shown to function as a nuclear import carrier of Hsp70 under heat-stress conditions. Knockdown of Hikeshi significantly enhances sensitivity to HT and mild HT in the presence — but not the absence — of heat-stress in human cancer cells. Moreover, upregulation of Hikeshi expression is observed in human gastric or renal cancer. It has also been suggested that functional defects leading to homozygosity for a missense mutation, p. Cys4Ser or p. Val54Leu, in Hikeshi cause leukoencephalopathy in Finnish or Ashkenazi-Jewish patients, respectively. This review summarizes the physiological and pathological roles of Hikeshi and discusses its potential as a target in HT therapy.