PGC1α: Friend or Foe in Cancer?

Mastropasqua, Francesca; Girolimetti, Giulia; Shoshan, Maria C.

doi:10.3390/genes9010048

Cited by 75 publications

(62 citation statements)

References 125 publications

(243 reference statements)

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“…Moreover, the activity of PGC1α-ERRα negatively correlated with levels of oncogenic transcription factor MYC [98]. However, it has to be added that the effect of PGC1α differs across various tumors (for review, see [99]). A metabolomics analysis of triple-negative breast cancer cells with an elevated level of MYC demonstrated a four-fold increase in production of palmitoylcarnitine when compared to control mammary gland.…”

Section: Slc22a5 and Fatty Acid Oxidation In Cancermentioning

confidence: 99%

SLC22A5 (OCTN2) Carnitine Transporter—Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer

Juraszek

Nałęcz

2019

Molecules

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Oxidation of fatty acids uses l-carnitine to transport acyl moieties to mitochondria in a so-called carnitine shuttle. The process of β-oxidation also takes place in cancer cells. The majority of carnitine comes from the diet and is transported to the cell by ubiquitously expressed organic cation transporter novel family member 2 (OCTN2)/solute carrier family 22 member 5 (SLC22A5). The expression of SLC22A5 is regulated by transcription factors peroxisome proliferator-activated receptors (PPARs) and estrogen receptor. Transporter delivery to the cell surface, as well as transport activity are controlled by OCTN2 interaction with other proteins, such as PDZ-domain containing proteins, protein phosphatase PP2A, caveolin-1, protein kinase C. SLC22A5 expression is altered in many types of cancer, giving an advantage to some of them by supplying carnitine for β-oxidation, thus providing an alternative to glucose source of energy for growth and proliferation. On the other hand, SLC22A5 can also transport several chemotherapeutics used in clinics, leading to cancer cell death.

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Section: Slc22a5 and Fatty Acid Oxidation In Cancermentioning

confidence: 99%

SLC22A5 (OCTN2) Carnitine Transporter—Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer

Juraszek

Nałęcz

2019

Molecules

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“…Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is a transcriptional coactivator that was initially identified in an interaction with nuclear receptor peroxisome proliferator-activated receptors (PPARγ) in response to lower temperatures [1]. In addition to its role in adaptive thermogenesis, PGC-1α is presently described as a master regulator of mitochondrial biogenesis and function, including oxidative phosphorylation (OXPHOS) and reactive oxygen species (ROS) detoxification [2]. In recent years, PGC-1α has been associated with many inflammatory and meta-bolic diseases, and its crucial role regulating mitochondrial function, oxidative stress, and metabolic pathways in diverse tissues has been revealed [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

Rius‐Pérez

Torres-Cuevas

Millán

et al. 2020

Oxidative Medicine and Cellular Longevity

406

292

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Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is a transcriptional coactivator described as a master regulator of mitochondrial biogenesis and function, including oxidative phosphorylation and reactive oxygen species detoxification. PGC-1α is highly expressed in tissues with high energy demands, and it is clearly associated with the pathogenesis of metabolic syndrome and its principal complications including obesity, type 2 diabetes mellitus, cardiovascular disease, and hepatic steatosis. We herein review the molecular pathways regulated by PGC-1α, which connect oxidative stress and mitochondrial metabolism with inflammatory response and metabolic syndrome. PGC-1α regulates the expression of mitochondrial antioxidant genes, including manganese superoxide dismutase, catalase, peroxiredoxin 3 and 5, uncoupling protein 2, thioredoxin 2, and thioredoxin reductase and thus prevents oxidative injury and mitochondrial dysfunction. Dysregulation of PGC-1α alters redox homeostasis in cells and exacerbates inflammatory response, which is commonly accompanied by metabolic disturbances. During inflammation, low levels of PGC-1α downregulate mitochondrial antioxidant gene expression, induce oxidative stress, and promote nuclear factor kappa B activation. In metabolic syndrome, which is characterized by a chronic low grade of inflammation, PGC-1α dysregulation modifies the metabolic properties of tissues by altering mitochondrial function and promoting reactive oxygen species accumulation. In conclusion, PGC-1α acts as an essential node connecting metabolic regulation, redox control, and inflammatory pathways, and it is an interesting therapeutic target that may have significant benefits for a number of metabolic diseases.

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“…The role of PGC1α in carcinogenesis has not been clear. Most experts believe early in carcinogenesis, PGC1α may be downregulated, while in the later stages of tumour progression, PGC1α is often upregulated [44]. A study in mice showed that PGC1α regulates mitochondrial function and promotes tumour growth [45].…”

Section: Discussionmentioning

confidence: 99%

Fasting Induces Hepatocellular Carcinoma Cell Apoptosis by Inhibiting SET8 Expression

Chen

et al. 2020

Oxidative Medicine and Cellular Longevity

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Background. Hepatocellular carcinoma (HCC) is a life-threatening cancer, and the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signalling pathway plays a crucial role in apoptosis resistance in cancer cells. Fasting is reported to mediate tumour growth reduction and apoptosis. SET8 is involved in cancer proliferation, invasiveness, and migration. However, whether SET8 participates in fasting-mediated apoptosis in HCC remains unclear. Methods. We used immunohistochemical staining to analyse the expression of SET8, Keap1, and Nrf2 in HCC tissues. Cell viability, apoptosis, and cellular reactive oxygen species (ROS) were assessed, and Western blot and qPCR analyses were used to examine the expression of Keap1/Nrf2 in HCC cells under fasting, SET8 overexpression, and PGC1α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1α interacts with SET8. In vivo experiments were performed to verify the conclusions from the in vitro experiments. Results. Our data indicate that SET8 expression is associated with poor survival in HCC patients. Both in vitro and in vivo results demonstrated that fasting decreased cell viability and downregulated expression of SET8, Nrf2, and downstream effectors of Nrf2, while it upregulated Keap1 expression, mediated ROS accumulation, and induced HCC cell apoptosis. These results were similar to what is observed in SET8-deficient cells. Furthermore, SET8 was found to interact with PGC1α, and both PGC1α and H4K20me1, a downstream target of SET8, were found to be enriched at the Keap1 promoter region. These two factors were further determined to attenuate Keap1 promoter activity. Conclusions. The results of our study demonstrate that fasting induces HCC apoptosis by inhibiting SET8 expression and that SET8 interacts with PGC1α to activate the Nrf2/ARE signalling pathway by inhibiting Keap1 expression.

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PGC1α: Friend or Foe in Cancer?

Cited by 75 publications

References 125 publications

SLC22A5 (OCTN2) Carnitine Transporter—Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer

SLC22A5 (OCTN2) Carnitine Transporter—Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

Fasting Induces Hepatocellular Carcinoma Cell Apoptosis by Inhibiting SET8 Expression

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