Parkin in Parkinson’s Disease and Cancer: a Double-Edged Sword

Abstract

Parkin for more than a decade has been portrayed as a neuroprotector gene is now increasingly emerging as a multifaceted gene that can exert entirely opposite effects i.e., both cell proliferation and apoptosis. Parkinson's disease, a neurological disease, progresses due to excess in cell death, while, in case of cancer, cell death normally fails to occur. Parkin, an E3 ubiquitin ligase, was first identified as a gene implicated in autosomal recessive juvenile Parkinsonism, but several evidences indicate that Parkin is a tumor suppressor gene, involved in a variety of cancers. It is hard to imagine that two entirely different classes of disease, like cancer and Parkinson's disease, can converge at a critical point attributable to a single gene, Parkin. This mysterious and hidden connection may prove a boon in disguise and has raised hopes that studying the biology of one disease may help to identify novel targets of therapy for the other. In this Parkinson's disease-cancer story, if the detail of Parkin pathway is unraveled and gaps in the storyline are properly filled up, we may end getting an entirely new therapeutic option. This review mainly highlights the recent literature which suggests how Parkin gene regulates the various hallmarks of both the Parkinson's disease and cancer.

Mdm2 enhances ligase activity of parkin and facilitates mitophagy

“…Furthermore, the role of parkin in promoting the mitochondria biogenesis has been demonstrated in neuronal cells and in the brain of living animals 67,68 , and the conditional knockout of parkin results in the loss of mitochondria and resulting neuronal degeneration 68 . HeLa cells used in this study have been derived from cervical cancer cells and lack parkin, as do many cancer cells, in which parkin acts as a tumor suppressor 69,70 . We show that Mdm2 enhances parkin's ligase activity and parkin-dependent ubiquitination of mitofusin-1, one of the key regulators of mitophagy 71 .Thus, the most straightforward interpretation of the evidence is that Mdm2 facilitates parkin-dependent mitophagy.…”

Neurodegenerative diseases and cancer: sharing common mechanisms in complex interactions

“…Interestingly, it is observed that Parkin influences the expression of the VEGF receptor (VEGFR). In Parkin cells, expression of VEGFR is found to be reduced when compared with controls (Kerbel and Kamen, 2004;Sherwood et al, 1971;Wahabi et al, 2018;Waltenberger et al, 1994), through an unknown mechanism.…”

“…Ample evidence suggests that Parkin is a tumor suppressor gene, involved in a variety of cancers (Cesari et al, 2003;Denison et al, 2003;Picchio et al, 2004;Wahabi et al, 2018;Wang et al, 2004). Parkin is an E3 ubiquitin-protein ligase, which ubiquitinates a large number of proteins, including itself, to promote different pathways, including ubiquitin -proteasomal pathway, and mitophagy.…”

“…As mentioned previously, Parkin has been identified as a tumor suppressor gene, and in order with this characteristic, its expression has been reported to be decreased in a variety of tumor biopsies and tumor cell lines. Although the role of Parkin in other cancers, such as breast cancer, is still to be explored, reports are stating a loss of Parkin expression and increased Parkin methylation in those tumors with the worst prognosis related to metastasis and neoplasm growth (Wahabi et al, 2018).…”

“…(Fig. 3) Another analysis point involves mitochondria (Engel, 2016;Wahabi et al, 2018). Its dysfunction in oxidative phosphorylation may be viewed more as facilitating rather than causing idiopathic PD since energy failure backs up the influence of additional agerelated, genetic and environmentally determining factors that lead to disease expression (Palacino et al, 2004;Schmidt et al, 2011).…”