Elevation of major constitutive heat shock proteins is heat shock factor independent and essential for establishment and growth of Lgl loss and Yorkie gain mediated tumors in Drosophila

Abstract

Cancer cells experience a variety of stresses like hypoxia, lack of nutrients, DNA damage and immune responses, which trigger several processes to drive genomic instability and mutation, alterations in gene expression programs, and reprogramming of the metabolic pathways to escape growth inhibition signaling, and acquire resistance to the immune surveillance. Different heat shock proteins are expressed at elevated levels in cancer cells. However, their specific roles in initiation, establishment and progression of cancers are still not clear. Here using the loss of function allele of the apico-basal polarity gene, lgl, we have established models for induction of tumorous somatic clones of different genetic constitutions at defined developmental times for examination of temporal and spatial patterns of expression of the major heat shock protein families, namely Hsp83, Hsp70, Hsp60 and Hsp27. The Hsp83, Hsp60 and Hsp27 begin to express in all cells of the tumor at high levels since early stages (48hr after tumor induction) and continue their high expression at later stages when the tumorous clones accumulate F-actin and get transformed. Levels of the heat shock cognate Hsc70 proteins also follow the same pattern as the other Hsps. However, the major stress-inducible Hsp70 is not expressed at early stages of tumor growth, but expresses at a later stage only in a few cells in a given lgl loss of function clone, which also shows high F-actin aggregates. Thus, the major Hsps, except the Hsp70, seems to be involved in early as well as late stages of epithelial tumors induced by loss of the Lgl cell polarity protein, while the Hsp70 expression in a few cells coincides with their getting transformed. This model will be useful for further genetic studies to dissect specific roles of different Hsps in tumor development and their therapeutic manipulation.