VDAC upregulation and αTAT1‑mediated α‑tubulin acetylation contribute to tanespimycin‑induced apoptosis in Calu‑1 cells.

Abstract

Voltage‑dependent anion channel 1 (VDAC1) functions as a porin in the mitochondrial outer membrane (MOM) and plays important roles in mitochondria‑mediated cell apoptosis. VDAC1 interacts with a variety of proteins, such as Bcl‑2 family proteins, hexose kinase (HK), adenine nucleotide translocase (ANT) and α‑tubulin. However, the association between VDAC1 and α‑tubulin, particularly between VDAC1 and acetylated α‑tubulin (Ac‑α‑tubulin), in apoptosis remains unclear. The present study revealed that the heat shock protein 90 inhibitor, tanespimycin, induced VDAC1 upregulation and α‑tubulin acetylation during Calu‑1 cell apoptosis in human lung cancer. Hsp90 mediated the expression level of VDAC1, and the acetylation of α‑tubulin was enhanced in an α‑tubulin acetyltransferase 1 (αTAT1)‑dependent manner following an increase in VDAC1 expression. Docetaxel, as an inhibitor of microtubules, augmented the expression of Ac‑α‑tubulin, VDAC1 and Bax induced by tanespimycin and increased the degree of caspase activation. Immunoprecipitation (IP) experiments revealed that Ac‑α‑tubulin, α‑tubulin and VDAC1 were co‑precipitated in the IP complex, in which α‑tubulin expression was decreased and VDAC1 proteins were oligomerized, and that the p‑AKT/glycogen synthase kinase 3β (GSK3β) signalling pathway mediated the opening of VDAC1. Therefore, it can be asserted that the acetylation of α‑tubulin and VDAC1 upregulation or oligomerization induced by tanespimycin may lead to mitochondrial permeability and consequently induce the apoptosis of lung cancer cells. These findings provide evidence for the use of a combination of drugs that target VDAC1 and tubulin to induce tumour cell apoptosis.