Von Hippel-Lindau regulates interleukin-32β stability in ovarian cancer cells

Abstract

Hypoxia-induced interleukin-32β (IL-32β) shifts the metabolic program to the enhanced glycolytic pathway. In the present study, the underlying mechanism by which hypoxia-induced IL-32β stability is regulated was investigated in ovarian cancer cells. IL-32β expression increased under hypoxic conditions in ovarian cancer cells as it did in breast cancer cells. The amount of IL-32β was regulated by post-translational control rather than by transcriptional activation. Under normoxic conditions, IL-32β was continuously eliminated through ubiquitin-dependent degradation by the von-Hippel Lindau (VHL) E3 ligase complex. Oxygen deficiency or reactive oxygen species (ROS) disrupted the interaction between IL-32β and VHL, leading to the accumulation of the cytokine. The fact that IL-32β is regulated by the energy-consuming ubiquitination system implies that it plays an important role in oxidative stress. We found that IL-32β reduced protein kinase Cδ (PKCδ)-induced apoptosis under oxidative stress. This implies that the hypoxia- and ROS-stabilized IL-32β contributes to sustain survival against PKCδ-induced apoptosis.

Molecular interactions and functions of IL-32

“…IL-32 is also induced during oxidative stress. 24,[77][78][79] In malignant plasma cells, the increase of IL-32 in response to hypoxia was dependent on hypoxia inducible factor 1-alpha (HIF1 ). 24 In ovarian cancer cells, hypoxia-induced reactive oxygen species (ROS) promoted accumulation of IL-32 .…”

“…Others have showed that in ovarian cancer cells IL‐32β stability is directly regulated by von‐Hippel Lindau (VHL) E3 ligase and that hypoxia‐induced ROS promoted accumulation of IL‐32β. IL‐32β formed a trimeric complex with VHL and PKCδ in normal oxygen levels resulting in a continuous degradation of IL‐32, and when stabilized by hypoxia, IL‐32 prevented PKCδ from inducing oxidative stress‐induced apoptosis 78 . Finally, IL‐32θ could bind PKCδ and STAT3 in PMA‐stimulated THP‐1 cells, phosphorylating STAT3 at the Ser727.…”

“…24 In ovarian cancer cells, hypoxia-induced reactive oxygen species (ROS) promoted accumulation of IL-32 . 78 Importantly, a recent game changing publication by Masson et al described the regulation of IL-32 by a novel oxygen sensing system. The thiol oxidase, cysteamine 2-aminoethanethiol dioxygenase (ADO), regulates the stability of IL-32 by deoxygenation of the N-terminal cysteine.…”

Interleukin-32: Frenemy in cancer?

“…On the other hand, hypoxia-induced IL-32β interacts with protein kinase C δ (PKCδ) and this interaction results in the suppression of PKCδ-induced apoptosis (52). We also showed that the accumulated IL-32β translocates to the mitochondria under hypoxic conditions.…”

VHL and Hypoxia Signaling: Beyond HIF in Cancer

“…MAVS and KLF4 are VHL substrates, but whether these regulations are dependent on oxygen availability is unknown [ 63 , 68 ]. The oxygen/VHL-mediated ubiquitination and proteasome degradation of proteins involve EGFR, atypical protein kinase C, Sprouty 2, β-adrenergic receptor II, Myb-binding protein 160, RPB1, RPB7, Cep68, Interleulin-32β, CERKL, FLNA, and ERK5/BMK1 [ 64 , 65 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ]. In addition, VHL transcriptionally regulates aldehyde dehydrogenase 2 ( ALDH2 ) through the direct activation of transcription factor HNF-4α in an HIF- and VHL E3 ligase-independent fashion, which contributes to the sensitivity of ccRCC cells to anthracycline treatment [ 80 ].…”