Hsp72 mediates TAp73α anti-apoptotic effects in small cell lung carcinoma cells.
Bottom Line: However, the precise mechanism by which TAp73α exerts its pro-survival effect is yet unclear.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.
Affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.Show MeSH
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Mentions: Etoposide was shown to induce destabilization of lysosomes , an event which in turn can trigger Bax activation in a cathepsin B dependent manner . On the other hand, lysosomal permeabilization has been shown to depend on Bax [32, 33]. Both ways, the destabilization of and subsequent leakage from lysosomal compartments can be prevented by simultaneous co-expression of Hsp72 . Significant LMP in H82 cells upon VP16 treatment is observed by FACS analysis at 24 hrs after exposure (Fig. S1C). Hence, we set out to determine whether TAp73α can prevent VP16-induced LMP in H82 cells, and further, if this event is mediated by Hsp72. Hence, we made use of LysoTracker dye which accumulates inside acidic organelles, such as lysosomes and late endosomes . A decreased LysoTracker fluorescence may then reflect LMP and/or an increase in lysosomal pH, which then would lead to less cytosolic puncta , as seen using fluorescence microscopy (Fig. 6C, compare white arrows in merge). Quantification of cells with a reduced punctiform staining, or no LysoTracker staining at all (here denoted as LMP), showed that VP16 treatment induced LMP (Fig. 6A). TAp73α was able to prevent VP16-induced LMP; however, co-transfection of TAp73α with asHsp72 and VP16 treatment resulted in LMP comparable to VP16 alone. On the other hand, TAp73β promoted VP16-induced LMP (Fig. 6B), whereas simultaneous co-transfection with Hsp72 resulted in a very little LMP, comparable to control levels. Given together, these results suggests that TAp73α induced Hsp72 expression protects the cell from drug-induced mitochondrial dysfunctions as well as LMP.
Affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.