Dehydroepiandrosterone triggers autophagic cell death in human hepatoma cell line HepG2 via JNK-mediated p62/SQSTM1 expression

Abstract

Autophagy is a catabolic process that cancer cells usually exploit during stress conditions to provide energy by recycling organelles and proteins. Beyond its prosurvival role, it is well accepted that occurrence of autophagy is often associated with a particular type of programmed cell death known as autophagic cell death (ACD). Dehydroepiandrosterone (DHEA) is an endogenous hormone showing anticancer properties even if the underlying mechanisms are not fully clear yet. Here, we provide evidence that DHEA induces ACD in human hepatoma cell line, HepG2. Indeed, autophagy inhibitors (i.e. 3-methyladenine or Atg5 siRNA) significantly reduced the percentage of dead cells. DHEA induces p62-dependent autophagy, which turns detrimental and brings about death. DHEA stimulates reactive oxygen species-independent jun N-terminal kinase (JNK) phosphoactivation and the treatment with JNK inhibitor reduces p62 mRNA levels, as well as DHEA-induced ACD. The transcription factor nuclear factor (erythroid-derived-2)-like-2 (Nrf2) constitutes the link between JNK and p62 since its migration to the nucleus is suppressed by JNK inhibitor and its inhibition through a dominant negative Nrf2 plasmid transfection decreases p62 protein levels. Overall, our data indicate that DHEA induces ACD in HepG2 via a JNK-Nrf2-p62 axis. Thus, DHEA could represent a new appealing drug for eliminating tumor cells through autophagy particularly in apoptosis-resistant cases.

p62/SQSTM1—Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer

“…SQSTM1 gene transcription is induced by NRF2 and NF‐κB , both of which are also activated by p62, thus establishing two interlocked positive feedback loops. SQSTM1 mRNA expression is also regulated by Ras‐ERK and JNK signaling as well as by miR‐372 and the nuclear hormone receptor farnesoid X receptor (FXR) . In addition to inflammation and oxidative stress, which activate NF‐κB and NRF2, respectively, SQSTM1 mRNA expression is induced by endoplasmic reticulum (ER) stress .…”

Cr(VI)-Induced Autophagy Protects L-02 Hepatocytes from Apoptosis Through the ROS-AKT-mTOR Pathway

“…With developments in research, investigators have found that the role autophagy plays in cell death varies greatly in different cell types and disease states. In glioma cells, ceramide can induce autophagy via the JNK-c-Jun pathway, causing autophagic cell death [42]. Liu et al reported an autophagy dependent but apoptotic independent cell death characterized by cell matrix adhesion and endoplasmic reticulum expansion, named autosis [43].…”

Is Melanoma a Hormone-Dependent Cancer or a Hormone-Responsive Cancer?

“…After having ruled out necrosis and apoptosis as the mechanism of inhibition of cell growth, it was found out that autophagy was the cause for cell growth inhibition by co-incubating progesterone and 3-methyl adenine (3-MA) on melanoma cells. 3-methyl adenine (3-MA) had been used in various studies to check or Cancer Prognosis inhibit autophagy [47][48][49]. Therefore, the mechanism of inhibition of human melanoma cell growth by progesterone was due to autophagy ( Figure 6).…”

“…Adhesion and migration assays suggested that progesterone could be playing a role in delayed metastasis, as reported in clinical studies [9] (Figure 7). to disrupt the formation of autophagsome/lysosomal degradation in various studies [47][48][49].…”