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Fatty Acid‐Induced Hepatocellular Carcinoma Growth is Mediated by Decreasing Mitochondrial H 2 O 2 Emission Coupled to Increased Glutathione Levels
Author(s) -
Turnbull Patrick C.,
Dehghani Ali C.,
Perry Christopher G. R.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.652.20
Subject(s) - glutathione , chemistry , context (archaeology) , population , clonogenic assay , endocrinology , medicine , biology , biochemistry , apoptosis , paleontology , environmental health , enzyme
Rationale and Hypothesis High fat diets are associated with increased hepatocellular carcinoma (HCC) risk, as well as increased HCC growth rates. Accelerated HCC growth in response to fatty acid challenges has been attributed to a variety of signalling pathways, but the role of metabolic and redox flexibility in mediating a pro‐growth environment in this context has not been examined. Here we examined the direct effect of fatty acid challenges on HCC growth in relation to altered metabolic and redox homeostasis. Experimental approach The HCC cell line HepG2 was incubated with 0μM, 50μM and 100μM palmitoylcarnitine (PCarn) for up to 48 hrs. We measured clonogenic survival, mitochondrial H 2 O 2 emission and glutathione following PCarn incubations with and without the glutathione depleting agent buthionine sulfoximine (BSO) and inhibition of uncoupling protein‐2 (UCP2) activity by genipin. Results 100μM PCarn increased clonogenic survival in HepG2 by 8% more than control (p<0.05) at 48 hrs which represents a marked early effect considering the population doubling time of HepG2 cells is ~48 hrs. This was associated with an increase in both reduced and oxidized glutathione at both 24 and 48 hrs (p<0.05). Depleting glutathione with BSO prevented PCarn‐stimulated growth (p<0.05). In a separate experiment, acute incubations of 100μM PCarn increased H 2 O 2 emission within the first 10 minutes (p<0.05) followed by a decrease in H 2 O 2 at 1 hr that remained lower at 24 hrs (p<0.05). The acute increase in H 2 O 2 followed by a more chronic depression in H 2 O 2 suggested PCarn might have triggered a compensatory mechanism. In support of this notion, inhibition of UCP2 with genipin sensitized HepG2 cells to PCarn‐induced decreases in clonogenic survival (p<0.05) without a change in UCP2 protein content. Conclusion Collectively, this data suggests that PCarn‐induced HCC growth is in part attributed to elevated glutathione. Increases in glutathione may be a result of UCP2 rapidly attenuating PCarn‐induced H 2 O 2 emission which may permit greater glutathione synthetic rates and creation of a pro‐growth redox environment. Support or Funding Information Funding was provided to C.G.R.P. by National Science and Engineering Research Council (#436138‐2013) with infrastructure supported by Canada Foundation for Innovation, Ontario Research Fund and the James H. Cummings Foundation. P. C. T. was supported by an NSERC CGS‐D scholarship. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .