Non-canonical BAD activity regulates breast cancer cell and tumor growth via 14-3-3 binding and mitochondrial metabolism

被引：0
作者：
Jasdeep Mann
John Maringa Githaka
Timothy W. Buckland
Ning Yang
Rachel Montpetit
Namrata Patel
Lei Li
Shairaz Baksh
Roseline Godbout
Hélène Lemieux
Ing Swie Goping
机构：
[1] University of Alberta,Department of Biochemistry
[2] University of Alberta,Department of Oncology
[3] University of Alberta,Department of Pediatrics
[4] University of Alberta,Department of Medicine
[5] University of Alberta,Faculty Saint
来源：
Oncogene | 2019年 / 38卷
关键词：
D O I：
暂无
中图分类号：
学科分类号：
摘要：
The Bcl-2-associated death promoter BAD is a prognostic indicator for good clinical outcome of breast cancer patients; however, whether BAD affects breast cancer biology is unknown. Here we showed that BAD increased cell growth in breast cancer cells through two distinct mechanisms. Phosphorylation of BAD at S118 increased S99 phosphorylation, 14-3-3 binding and AKT activation to promote growth and survival. Through a second, more prominent pathway, BAD stimulated mitochondrial oxygen consumption in a novel manner that was downstream of substrate entry into the mitochondria. BAD stimulated complex I activity that facilitated enhanced cell growth and sensitized cells to apoptosis in response to complex I blockade. We propose that this dependence on oxidative metabolism generated large but nonaggressive cancers. This model identifies a non-canonical role for BAD and reconciles BAD-mediated tumor growth with favorable outcomes in BAD-high breast cancer patients.
引用
收藏
页码：3325 / 3339
页数：14
相关论文
共 253 条
  • [21] Fisher JK(1999)p90(RSK) blocks bad-mediated cell death via a protein kinase C-dependent pathway J Biol Chem 274 34859-67
  • [22] Szlyk B(1996)Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L) Cell 87 619-28
  • [23] Polak K(2001)The growth-promoting activity of the Bad protein in chicken embryo fibroblasts requires binding to protein 14-3-3 Oncogene 20 5087-92
  • [24] Wiwczar J(2001)14-3-3 inhibits Bad-induced cell death through interaction with serine-136 Mol Pharmacol 60 1325-31
  • [25] Ranger AM(1997)Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis Proc Natl Acad Sci USA 94 3668-72
  • [26] Zha J(2005)Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins Genes Dev 19 1294-305
  • [27] Harada H(2001)BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest Oncogene 20 4507-18
  • [28] Datta SR(2002)The proapoptotic BH3-only protein BAD transduces cell death signals independently of its interaction with Bcl-2 Cell Death Differ 9 1240-7
  • [29] Danial NN(2000)Mammalian hexokinases and their abnormal expression in cancer Br J Biomed Sci 57 170-8
  • [30] Gilmore AP(2006)Hexokinase II: cancer’s double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria Oncogene 25 4777-86
12345678910