Reactive Oxygen Species and Mitochondrial Sensitivity to Oxidative Stress Determine Induction of Cancer Cell Death by p21

Masgras, Ionica; Carrera, Samantha; Verdier, Petra J. de; Brennan, Paul; Majid, Aneela; Makhtar, Wan Ratmaazila Wan; Tulchinsky, Eugene; Jones, George D.D.; Roninson, Igor B.; Macip, Salvador

doi:10.1074/jbc.m111.250357

Cited by 82 publications

(59 citation statements)

References 46 publications

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“…ROS and the p21 protein have also been implicated in activating apoptosis, both of which increased in response to compound 1 (Figs. 2C and 3B) (31).…”

Section: Resultsmentioning

confidence: 99%

Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells

Hearn

Romero‐Canelón

Munro

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The organometallic “half-sandwich” compound [Os(η6-p-cymene)(4-(2-pyridylazo)-N,N-dimethylaniline)I]PF6 is 49× more potent than the clinical drug cisplatin in the 809 cancer cell lines that we screened and is a candidate drug for cancer therapy. We investigate the mechanism of action of compound 1 in A2780 epithelial ovarian cancer cells. Whole-transcriptome sequencing identified three missense mutations in the mitochondrial genome of this cell line, coding for ND5, a subunit of complex I (NADH dehydrogenase) in the electron transport chain. ND5 is a proton pump, helping to maintain the coupling gradient in mitochondria. The identified mutations correspond to known protein variants (p.I257V, p.N447S, and p.L517P), not reported previously in epithelial ovarian cancer. Time-series RNA sequencing suggested that osmium-exposed A2780 cells undergo a metabolic shunt from glycolysis to oxidative phosphorylation, where defective machinery, associated with mutations in complex I, could enhance activity. Downstream events, measured by time-series reverse-phase protein microarrays, high-content imaging, and flow cytometry, showed a dramatic increase in mitochondrially produced reactive oxygen species (ROS) and subsequent DNA damage with up-regulation of ATM, p53, and p21 proteins. In contrast to platinum drugs, exposure to this organo-osmium compound does not cause significant apoptosis within a 72-h period, highlighting a different mechanism of action. Superoxide production in ovarian, lung, colon, breast, and prostate cancer cells exposed to three other structurally related organo-Os(II) compounds correlated with their antiproliferative activity. DNA damage caused indirectly, through selective ROS generation, may provide a more targeted approach to cancer therapy and a concept for next-generation metal-based anticancer drugs that combat platinum resistance.

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“…ROS and the p21 protein have also been implicated in activating apoptosis, both of which increased in response to compound 1 (Figs. 2C and 3B) (31).…”

Section: Resultsmentioning

confidence: 99%

Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells

Hearn

Romero‐Canelón

Munro

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Additionally, the expression of p21 following DNA damage has been shown to be both p53 dependent and p53 independent (2,10,11,16,34,59) and to be p53 and Klf4 dependent in vitro (19,63). Also, p21 levels have been shown to have a dose-dependent and a cell-cycle dependent effect on the apoptotic or antiapoptotic cell fate (1,32,35,41). Furthermore, results of DNA-damage repair (Fig.…”

Section: Discussionmentioning

confidence: 99%

Krüppel-like factor 4 is a radioprotective factor for the intestine following γ-radiation-induced gut injury in mice

Talmasov

Zhang

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…41 According to our results, Stra6 could be more effective as an enhancer of apoptosis in cancer cells with higher sensitivity to oxidants, consistent with our previous results showing that cell-specific sensitivity to oxidative stress can determine the induction of cell death instead of arrest. 42 Therefore, all these data suggests that retinoids could potentially be used as adjuvants Role of Stra6 in p53-dependent apoptosis S Carrera et al of chemo-and radiotherapy in tumours that retain responsiveness to RA and a certain functionality of the p53 pathway. This also anticipates that vitamin A, a relatively cheap and safe compound, could be successfully used in chemoprevention, as it would increase the basal levels of Stra6 expression and thus enhance the tumour suppressor functions of p53.…”

Section: Discussionmentioning

confidence: 99%

Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage

et al. 2013

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Stra6 is the retinoic acid (RA)-inducible gene encoding the cellular receptor for holo-retinol binding protein. This transmembrane protein mediates the internalization of retinol, which then upregulates RA-responsive genes in target cells. Here, we show that Stra6 can be upregulated by DNA damage in a p53-dependent manner, and it has an important role in cell death responses. Stra6 expression induced significant amounts of apoptosis in normal and cancer cells, and it was also able to influence p53-mediated cell fate decisions by turning an initial arrest response into cell death. Moreover, inhibition of Stra6 severely compromised p53-induced apoptosis. We also found that Stra6 induced mitochondria depolarization and accumulation of reactive oxygen species, and that it was present not only at the cellular membrane but also in the cytosol. Finally, we show that these novel functions of Stra6 did not require downstream activation of RA signalling. Our results present a previously unknown link between the RA and p53 pathways and provide a rationale to use retinoids to upregulate Stra6, and thus enhance the tumour suppressor functions of p53. This may have implications for the role of vitamin A metabolites in cancer prevention and treatment.

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Reactive Oxygen Species and Mitochondrial Sensitivity to Oxidative Stress Determine Induction of Cancer Cell Death by p21

Cited by 82 publications

References 46 publications

Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells

Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells

Krüppel-like factor 4 is a radioprotective factor for the intestine following γ-radiation-induced gut injury in mice

Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage

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