Cathepsin D protects colorectal cancer cells from acetate-induced apoptosis through degradation of damaged mitochondria

Authors and Affiliations:

Cláudia Suellen F. Oliveira (1,2), Helena Pereira (1), Sara Alves (1), Lisandra Castro (1), Fátima Baltazar (3,4), Susana R. Chaves (1), Ana Preto (1*), Manuela Côrte-Real (1*#)

(1) CBMA- Centro de Biologia Molecular e Ambiental. Departamento de Biologia, Universidade do Minho, Campus de Gualtar, 4710-057, Braga, Portugal.

(2) ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313, Porto, Portugal.

(3) Instituto de Ciências da Vida e da Saúde (ICVS), Escola de Ciências, Universidade do Porto, 4050-313, Porto, Portugal.

(4) ICVS/3B’s - Laboratório Associado do Governo PT, Braga/Guimarães, Portugal.

Abstract:

Acetate is a short-chain fatty acid secreted by Propionibacteria from the human intestine, known to induce mitochondrial apoptotic death in colorectal cancer (CRC) cells. We previously established that acetate also induces lysosome membrane permeabilization (LMP) in CRC cells, associated with release of the lysosomal protease Cathepsin D (CatD), which has a well-established role in the mitochondrial apoptotic cascade. Unexpectedly, we showed that CatD plays an anti-apoptotic role in this process, since pepstatin A (a CatD inhibitor) increased acetate-induced apoptosis. We found that, acetate-induced apoptosis is not associated with autophagy induction in CRC cells. Moreover, inhibition of CatD with siRNA or pepstatin A enhanced apoptosis associated with higher mitochondrial dysfunction and increased mitochondrial mass. This effect seems to be specific, since inhibition of Cathepsins B and L with E-64d had no effect, nor were these proteases significantly released to the cytosol during acetate-induced apoptosis.

In summary, we unveiled a novel CatD function in the degradation of damaged mitochondria when autophagy is impaired, which protects CRC cells from acetate-induced apoptosis. CatD inhibitors could therefore enhance acetate-mediated cancer cell death, presenting a novel strategy for prevention or therapy of CRC.

Journal: Cell Death and Disease

Link: http://www.nature.com/cddis/journal/v6/n6/full/cddis2015157a.html