Hsp72 mediates TAp73α anti-apoptotic effects in small cell lung carcinoma cells

Abstract

The transcription factor p73, a member of the p53 family of proteins, is involved in the regulation of cell cycle progression and apoptosis. Due to alternative promoters and carboxy-terminal splicing, the P73 gene gives rise to a range of different isoforms. Interestingly, a particular increase in expression of the TAp73α isoform has been reported in various tumours. In addition, TAp73α has been shown to inhibit Bax activation and mitochondrial dysfunctions and thereby to confer small cell lung carcinoma (SCLC) cells resistance to drug-induced apoptosis. However, the precise mechanism by which TAp73α exerts its pro-survival effect is yet unclear. Here we report that TAp73α, but not TAp73β, regulates the expression of inducible Hsp72/HSPA1A. Hsp72 proved to be required for the survival effects of TAp73α as antisense knockdown of Hsp72 resulted in an abolishment of the anti-apoptotic effect of TAp73α in SCLC cells upon Etoposide treatment. Importantly, depletion of Hsp72 allowed activation of Bax, loss of mitochondrial membrane potential and lysosomal membrane permeabilization in SCLC cells even in the presence of TAp73α. Finally, we revealed that TAp73β counteracts the anti-apoptotic effect of TAp73α by preventing Hsp72 induction. Our results thus provide additional evidence for the potential oncogenic role of TAp73α, and extend the understanding of the mechanism for its anti-apoptotic effect.

TAp73alpha protects small cell lung carcinoma cells from caspase-2 induced mitochondrial mediated apoptotic cell death

“…Previously, we have shown that TAp73alpha can repress drug-induced apoptosis in a cell-type specific manner. We demonstrated this effect to be exerted upstream of the mitochondria, at the level of Bax activation [22, 44]. Here, we provide an additional mechanism in support of the anti-apoptotic effect of TAp73alpha.…”

“…We have shown that TAp73alpha is able to prevent VP16-induced loss of mitochondrial membrane potential in SCLC cells [22, 44]. To explore whether the protective effect of TAp73alpha over-expression on caspase-2 induced apoptosis involve repression of mitochondrial dysfunction, the mitochondrial transmembrane potential was investigated.…”

“…We have previously shown that TAp73alpha is able to prevent Bax activation upon VP16 treatment [22, 44]. Thus, we decided to explore whether the protective effect of TAp73alpha over-expression on caspase-2 induced apoptosis is due to repression of Bax activation.…”

“…Moreover, the ability of over-expressed caspase-2 to promote apoptosis is established [ 34 , 43 ]. We have previously shown that full-length TAp73alpha represses drug-induced apoptosis in SCLC cells, upstream of the mitochondria at the level of Bax activation [ 22 , 44 ]. To test whether caspase-2 over-expression induces apoptosis in SCLC NCI-H82 cells and whether TAp73alpha can exert a repressive effect on caspase-2 induced cell death, apoptosis assays were performed.…”

Corrigendum

“…In Nyman et al . , an error occurred in Figure 1 Panel B. The G3PDH immunoblot presented for HEK293 cells is a duplication of the G3PDH immunoblot related to H82 cells.…”