Obatoclax induces Atg7-dependent autophagy independent of beclin-1 and BAX/BAK

McCoy, Francis; Hurwitz, Jane; McTavish, Niall; Paul, Ian; Barnes, Clifford A.; O'Hagan, Barry; Odrzywol, Krzysztofa; Murray, James T.; Longley, Daniel B.; McKerr, George; Fennell, Dean A.

doi:10.1038/cddis.2010.86

Cited by 84 publications

(101 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ectopic expression of MCL-1 or knockdown of NOXA diminished the potentiation of lapatinib lethality by obatoclax, and this result probably highlights a central role of the NOXA and MCL-1 interaction in autophagy initiation inhibition, together with BAX and BAK, whose activation was separate from that of NOXA. (Kang and Reynolds, 2009;McCoy et al, 2010). In the present study, lapatinib and obatoclax led to ROS generation, which was concomitant with loss of mitochondrial membrane potential.…”

Section: Discussionsupporting

confidence: 52%

Obatoclax and Lapatinib Interact to Induce Toxic Autophagy through NOXA

Tang¹,

Hamed²,

Cruickshanks³

et al. 2012

Mol Pharmacol

View full text Add to dashboard Cite

Prior studies demonstrated that resistance to the ERBB1/2 inhibitor lapatinib could be overcome by the B cell CLL/lymphoma-2 (BCL-2) family antagonist obatoclax (GX15-070). Coadministration of lapatinib with obatoclax caused synergistic cell killing by eliciting autophagic cell death that was dependent upstream on mitochondrial reactive oxygen species generation and increased p62 levels and downstream on activation of p38 mitogen-activated protein kinase and inactivation of mammalian target of rapamycin. By immunohistochemical analysis, in drug combination-treated cells, microtubule-associated protein light chain 3 (LC3) associated with mitochondrial (cytochrome c oxidase), autophagosome (p62), and autolysosome (lysosomal associated membrane protein 2) proteins. Treatment of cells with 3-methyladenine or knockdown of beclin 1 was protective, whereas chloroquine treatment had no protective effect. Expression of myeloid cell leukemia-1 (MCL-1), compared with that of BCL-2 or BCL-2-related gene long isoform, protected against drug combination lethality. Lapatinib and obatoclaxinitiated autophagy depended on NOXA-mediated displacement of the prosurvival BCL-2 family member, MCL-1, from beclin 1, which was essential for the initiation of autophagy. Taken together, our data argue that lapatinib and obatoclaxinduced toxic autophagy is due to impaired autophagic degradation, and this disturbance of autophagic flux leads to an accumulation of toxic proteins and loss of mitochondrial function.

show abstract

Section: Discussionsupporting

confidence: 52%

Obatoclax and Lapatinib Interact to Induce Toxic Autophagy through NOXA

Tang¹,

Hamed²,

Cruickshanks³

et al. 2012

Mol Pharmacol

View full text Add to dashboard Cite

show abstract

“…The efficacy of GX15-070 in reducing the ATP production of PHD3-underexpressing cells might however be explained by the fact that GX15-070 treatment downregulates the overall abundance of MCL-1 protein (41). Obviously, we do not want to rule out that GX15-070 affects ATP production in PHD3-underexpressing cells via mechanisms distinct from the effects of mitochondrial MCL-1 (42,43). Taken together, our analyses identified MCL-1 as a novel molecular player, regulating tumor cell metabolism and invasion downstream PHD3.…”

Section: Discussionmentioning

confidence: 94%

Prolyl Hydroxylase 3 Attenuates MCL-1–Mediated ATP Production to Suppress the Metastatic Potential of Colorectal Cancer Cells

et al. 2016

View full text Add to dashboard Cite

Hypoxia is a common feature of solid tumors. Prolyl hydroxylase enzymes (PHD1-3) are molecular oxygen sensors that regulate hypoxia-inducible factor activity, but their functions in metastatic disease remain unclear. Here, we assessed the significance of PHD enzymes during the metastatic spread of colorectal cancer. PHD expression analysis in 124 colorectal cancer patients revealed that reduced tumoral expression of PHD3 correlated with increased frequency of distant metastases and poor outcome. Tumorigenicity and metastatic potential of colorectal tumor cells over and underexpressing PHD3 were investigated in orthotopic and heterotopic tumor models. PHD3 overexpression in a syngeneic tumor model resulted in fewer liver metastases, whereas PHD3 knockdown induced tumor spread. The migration of PHD3-overexpressing tumor cells was also attenuated in vitro. Conversely, migratory potential and colony formation were enhanced in PHD3-deficient cells, and this phenotype was associated with enhanced mitochondrial ATP production. Furthermore, the effects of PHD3 deficiency were accompanied by increased mitochondrial expression of the BCL-2 family member, member myeloid cell leukemia sequence 1 (MCL-1), and could be reversed by simultaneous inhibition of MCL-1. MCL-1 protein expression was likewise enhanced in human colorectal tumors expressing low levels of PHD3. Therefore, we demonstrate that downregulation of PHD3 augments metastatic spread in human colorectal cancer and identify MCL-1 as a novel downstream effector of oxygen sensing. Importantly, these findings offer new insight into the possible, context-specific deleterious effects of pharmacologic PHD inhibition. Cancer Res; 76(8); 2219-30. Ó2016 AACR.

show abstract

“…In SH-SY5Y cells exposure to the neurotoxin 1-methyl-4-phenylpyridinium (MPP + ) provoked autophagy and cell death that were insensitive to PtdIns3K inhibition or Beclin 1 knockdown. 52,53 Likewise, autophagy that is insensitive to knockdown of Beclin 1 or of its binding partner hVps34 (i.e., class III PtdIns3K) is involved in the caspaseindependent death of cancer cells induced by resveratrol, 54 in the hydrogen peroxide induced death of GSH-depleted RAW 264.7 cells, 55 in the obatoclax-induced death of various cancer cells 56 and in HeLa cells treated with an inhibitor of the the BH3-binding groove of Bcl-X L /Bcl-2.…”

Section: Discussionmentioning

confidence: 99%