BNIP3 in Lung Cancer: To Kill or Rescue?

Abstract

Bcl-2/adenovirus E1B 19kDa interacting protein 3 (BNIP3) is a pro-apoptotic BH3-only protein of the Bcl-2 family. Initially, BNIP3 was described as one of the mediators of hypoxia-induced apoptotic cell death in cardiac myocytes and neurons. Besides apoptosis, BNIP3 plays a crucial role in autophagy, metabolic pathways, and metastasis-related processes in different tumor types. Lung cancer is one of the most aggressive types of cancer, which is often diagnosed at an advanced stage. Therefore, there is still urgent demand for reliable biochemical markers for lung cancer and its efficient treatment. Mitochondria functioning and mitochondrial proteins, including BNIP3, have a strong impact on lung cancer development and progression. Here, we summarized current knowledge about the BNIP3 gene and protein features and their role in cancer progression, especially in lung cancer in order to develop new therapeutic approaches associated with BNIP3.

The Interplay Between Tumor Suppressor p53 and Hypoxia Signaling Pathways in Cancer

“…Cells with deficiency of pro-apoptotic proteins Bax and Bak are resistant to hypoxia-induced apoptosis, whereas overexpression of anti-apoptotic proteins Bcl-2 or Bcl-XL prevents hypoxia-induced apoptosis by inhibiting the cytochrome c release ( McClintock et al, 2002 ; Moldoveanu and Czabotar, 2020 ). Severe hypoxia induces the expression of pro-apoptotic gene BNIP3 via HIF-1α, resulting in hypoxia-induced apoptosis ( Guo et al, 2001 ; Gorbunova et al, 2020 ). Under mild hypoxia, p53 directly suppresses BNIP3 expression to protect cells against hypoxia-induced apoptosis ( Feng et al, 2011 ).…”

“…Under mild hypoxia, p53 directly suppresses BNIP3 expression to protect cells against hypoxia-induced apoptosis ( Feng et al, 2011 ). Under severe hypoxia, p53 induces apoptosis through inducing the expression of another pro-apoptotic gene BNIP3L, a homolog of BNIP3, which contributes to the role of p53 in tumor suppression ( Fei et al, 2004 ; Gorbunova et al, 2020 ).…”

“…p53 was reported to facilitate autophagy by inducing the expression of DRAM, Sestrins, and AMPK and inhibiting the mTOR pathway ( Crighton et al, 2006 ; Feng and Levine, 2010 ; Xu-Monette and Young, 2012 ). BNIP3 and BNIP3L, which are induced under hypoxia via HIF-1α ( Gorbunova et al, 2020 ), also play important roles in promoting autophagy in addition to apoptosis ( Bellot et al, 2009 ; Daskalaki et al, 2018 ). Ectopic expression of BNIP3 and BNIP3L can activate autophagy by disrupting the Bcl-2–Beclin1 complex ( Bellot et al, 2009 ; Gorbunova et al, 2020 ).…”

“…BNIP3 and BNIP3L, which are induced under hypoxia via HIF-1α ( Gorbunova et al, 2020 ), also play important roles in promoting autophagy in addition to apoptosis ( Bellot et al, 2009 ; Daskalaki et al, 2018 ). Ectopic expression of BNIP3 and BNIP3L can activate autophagy by disrupting the Bcl-2–Beclin1 complex ( Bellot et al, 2009 ; Gorbunova et al, 2020 ). p53 induces BNIP3 expression and leads to autophagy ( Wang et al, 2013 ).…”

“…p53 induces BNIP3 expression and leads to autophagy ( Wang et al, 2013 ). Furthermore, p53 also induces expression of BNIP3L under hypoxia, which promotes autophagy ( Fei et al, 2004 ; Bellot et al, 2009 ; Gorbunova et al, 2020 ). However, the role of p53 in autophagy appears to be context dependent.…”