The AMPK–Parkin axis negatively regulates necroptosis and tumorigenesis by inhibiting the necrosome

Abstract

The receptor-interacting protein 1 (RIPK1)/RIPK3 kinases play important roles in necroptosis that is closely linked to inflammatory response. Although the activation of necroptosis is well characterized, how necroptosis is tuned down is largely unknown. Here, we found that Parkin (also known as PARK2 ), an E3 ubiquitin ligase implicated in Parkinson’s disease and a tumor suppressor, regulates necroptosis and inflammation by regulating necrosome formation. Parkin prevents the formation of the RIPK1-RIPK3 complex by promoting polyubiquitination of RIPK3. Parkin is phosphorylated and activated by the cellular energy sensor AMP-activated protein kinase (AMPK). Parkin-deficiency potentiates the RIPK1-RIPK3 interaction, RIPK3 phosphorylation, and necroptosis. Importantly, Parkin deficiency enhances inflammation and inflammation-associated tumorigenesis. These findings demonstrate that the AMPK-Parkin axis negatively regulates necroptosis via inhibiting the RIPK1-RIPK3 complex formation and this regulation may serve as an important mechanism to fine-tune necroptosis and inflammation.

The Links between Parkinson’s Disease and Cancer

“…PARK2 mutations may reduce the ubiquitinating ability for substrates such as α-synuclein or synphilin-1, leading to their toxic accumulation in the brain [ 104 , 105 ]. PARKIN also has anti-inflammatory effects, as PARKIN-knockout mice have an increased susceptibility to inflammation-related degeneration [ 106 ]. A lack of PARKIN inhibits the differentiation of neural stem cells by JNK-dependent (JNK-c-Jun N-terminal kinase) p21 proteasomal degradation [ 107 ].…”

“…In some cancer cells, necroptosis disorders and defects of important process effectors have been shown [ 131 , 132 , 133 ]. Based on their research, Lee et al [ 106 ] suggested that the AMPK (AMP-activated protein kinase)/Parkin/RIPK3 pathway is a vital regulatory mechanism for necroptosis and inflammation-induced tumorigenesis. They showed that PARKIN deficiency exacerbates inflammation and inflammation-associated tumorigenesis, which indicates the protective role of PARKIN in carcinogenesis.…”

Neurodegenerative diseases and cancer: sharing common mechanisms in complex interactions

“…The TNF activation is followed by subsequent phosphorylation of receptor-interacting serine/threonine-protein kinases 1 (RIPK1) and 3 (RIPK3), which are recruited into a complex called the necrosome. RIPK3 phosphorylates the mixed lineage kinase domain-like protein (MLKL), leading to its activation and membrane permeabilization, favoring the pro-inflammatory molecules (damage-associated molecular patterns-DAMPs) release, and thereby inhibiting carcinogenesis (Cao and Tait, 2019;Lee et al, 2019).…”

“…Interestingly, the authors provide evidence that Parkin activation in necroptosis occurs independently of PINK1-Parkinmediated mitophagy to remove damaged mitochondria. Beyond the classical role of parkin in mitophagy, they identified a role in the necroptosis inhibition mediated by AMP-activated protein kinase (AMPK) that increases RIPK3 polyubiquitylation affecting the RIPK1-RIPK3 interaction, one of the relevant steps for necroptosis (Lee et al, 2019).…”

“…(Fig. 2) Although anti-inflammatory and anti-tumor functions of Parkin are extensively recognized, PARK2 heterozygosity has been described to be associated with colorectal tumor progression in experimental models (Lee et al, 2019). Cancer cell survival might be explained by their capacity to impair the activity and expression of tumor suppressor genes, such as PTEN (phosphatase and tensin homolog) gene, which is known to be down-regulated in several cancers (Li et al, 1997).…”