Different roles of dFOXO and HSF in spatio-temporal dynamics of stress-inducible Hsp70 in lgl-yorkie & lgl-Ras driven epithelial tumours inDrosophila

Abstract

Oncogenic cells recruit diverse cellular survival machineries, including the highly conserved heat shock proteins (Hsps), to counter stressful conditions during tumour progression. Despite important roles of Hsps in several cancers, poor understanding of their regulation leaves major gaps in identifying mechanisms of cellular stress responses exploited by cancer cells. Following our earlier report of stress inducible Hsp70 expression only in a few cells in polarity defective tumorous clones, we now show that Hsp70 is expressed only in neoplastic tumours. Hsp70 expression at 72h after clone induction is mostly limited to a few lgl- ykiOE cells exhibiting mesenchymal features in hypoxic zone closer to tracheae, although all tumorous cells express hsp70 transcripts. Down-regulation of the hsp70a but not hsp70b cluster transcripts substantially suppresses growth of lgl- ykiOE clones without affecting their early establishment. However, over-expression of Hsp70 or Hsp70-cochaperone DnaJ suppress lgl- ykiOE clones growth at early stage. This spatially and temporally regulated expression of Hsp70 in lgl- ykiOE clones is independent of HSF but requires dFOXO and JNK signalling, while a nearly similar pattern of Hsp70 expression in lgl- RasV12 clones requires HSF, rather than dFOXO. Such context dependent Hsp70 regulation provides novel insight into stress regulatory machinery in cancer cells.