UCP2 upregulation promotes PLCγ‐1 signaling during skin cell transformation

Abstract

Uncoupling protein 2 (UCP2), whose physiological role is to decrease mitochondrial membrane potential and reactive oxygen species (ROS) production, is often overexpressed in human cancers. UCP2 upregulation has recently been proposed as a novel survival mechanism for cancer cells. However, until now, how exactly UCP2 promotes tumorigenesis remains inconclusive. Based on a widely used skin cell transformation model, our data demonstrated that UCP2 differentially regulated ROS. UCP2 upregulation decreased superoxide whereas it increased hydrogen peroxide production with concomitant increase in the expression and activity of manganese superoxide dismutase (MnSOD), the primary mitochondrial antioxidant enzyme. Furthermore, hydrogen peroxide was responsible for induction of lipid peroxidation, and PLCγ-1 activation in UCP2 overexpressed cells. Additionally, PLCγ-1 activation enhanced skin cell transformation, and pharmacological, and siRNA mediated inhibition of PLCγ-1, markedly reduced colony formation, and 3D cell growth. Moreover, hydrogen peroxide scavenger, catalase, suppressed lipid peroxidation, and dampened PLCγ-1 activity. Taken together, our data suggest that (i) UCP2 is an important regulator of mitochondrial redox status and lipid signaling; (ii) hydrogen peroxide might mediate UCP2’s tumor promoting activity; and (iii) pharmacological disruption of PLCγ-1 and/or hydrogen peroxide may have clinical utility for UCP2 overexpressed cancers.

UCP2 Overexpression Redirects Glucose into Anabolic Metabolic Pathways

“…The increased levels of UCP2 have been linked to enhanced cell proliferation and tumorigenicity . Furthermore, our results showed that UCP2 overexpression promoted skin tumorigenesis via altering glucose and lipid metabolism, and the key regulators of metabolic processes . As such, UCP2 is thought to be a crucial player in the cascade of molecular and metabolic events associated with carcinogenesis.…”

“…Murine skin epidermal cells (purchased from American Type Culture Collection, Manassas, VA) were the only well‐characterized skin cell model to study tumor promotion . Stable UCP2 overexpressing and control pCMV cells were generated as previously described . Briefly, JB6 P+ (CL‐41) cells were transfected with a human UCP2‐containing or an empty pCMV6 vector (purchased from OriGene, Rockville, MD; catalog number SC320879 and PS100001, respectively) and stable clones were established.…”

“…Therefore, to decipher the influence of UCP2 overexpression on cellular metabolism, we performed overall pathway analysis using the stable isotope‐resolved metabolomics (SIRM) approach . UCP2 overexpressing cells were generated by transfecting JB6 P+ cells with a human UCP2‐containing vector or an empty base vector (pCMV6) as described previously . UCP2 overexpressing and control pCMV cells were labeled with uniformly 13 C‐enriched glucose to “trace” the fate of carbon atoms derived from 13 C glucose.…”

“…[19,23] Furthermore, our results showed that UCP2 overexpression promoted skin tumorigenesis via altering glucose and lipid metabolism, and the key regulators of metabolic processes. [24,25] As such, UCP2 is thought to be a crucial player in the cascade of molecular and metabolic events associated with carcinogenesis. Although it remains unclear exactly how UCP2 elevation exerts its pro-tumorigenic effect at the molecular level, a growing body of evidence suggests that UCP2 plays an important role in tumor cell metabolic reprogramming.…”

UCP2 gene polymorphisms in obesity and diabetes, and the role of UCP2 in cancer

“…Using the same model, our group has also found that upregulated UCP2 enhances the signaling of PLCγ‐1 . In UCP2 overexpressing cells, the levels of superoxide are decreased, whereas that of hydrogen peroxide is increased, concomitantly with increased expression and activity levels of manganese superoxide dismutase.…”