Removal of the BH4 domain from Bcl-2 protein triggers an autophagic process that impairs tumor growth

Daniela Trisciuoglio, Teresa de Luca, Marianna Desideri, Daniela Passeri, Chiara Gabellini, Stefania Scarpino, Chengyu Liang, Augusto Orlandi, Donatella Del Bufalo

Research output: Contribution to journalArticlepeer-review

Abstract

Here, we show that forced expression of a B-cell lymphoma 2 (bcl-2) protein lacking residues 1 to 36 at the N-terminal, including the entire Bcl-2 homology 4 (BH4) domain, determines reduction of in vitro and in vivo human melanoma growth. Noteworthy, melanoma cells in vivo exhibit markedly increased autophagy, as response to expression of bcl-2 protein deleted of its BH4 domain. This observation led to the identification of a novel gain of function for bcl-2 protein lacking the BH4 domain. In particular, upon different autophagic stimuli in vitro, overexpression of bcl-2 protein deleted of BH4 domain induces autophagosome accumulation, conversion of microtubule-associated protein 1 light chain 3B-II, reduced expression of p62/SQSTM1 protein, and thereby enhanced autophagic flux. The relevance of Beclin-1 is evidenced by the fact that 1) the autophagy-promoting and growth-inhibiting properties are partially rescued by Beclin-1 knockdown in cells expressing bcl-2 protein lacking the BH4 domain, 2) Beclin-1 only interacts with wild-type but not with deleted bcl-2, and 3) BH4 domain removal from bcl-2 protein does not influence in vitro and in vivo growth of tumor cells expressing low levels of endogenous Beclin-1. These results provide new insight into molecular mechanism of bcl-2 functions and represent a rationale for the development of agents interfering with the BH4 domain of bcl-2 protein.

Original languageEnglish
Pages (from-to)315-327
Number of pages13
JournalNeoplasia (United States)
Volume15
Issue number3
DOIs
Publication statusPublished - 2013

ASJC Scopus subject areas

  • Cancer Research

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