Downregulation of ASPP2 improves hepatocellular carcinoma cells survival via promoting BECN1-dependent autophagy initiation

Abstract

Autophagy is an important catabolic process, which sustains intracellular homeostasis and lengthens cell survival under stress. Here we identify the ankyrin-repeat-containing, SH3-domain-containing, and proline-rich region-containing protein 2 (ASPP2), a haploinsufficient tumor suppressor, as a molecular regulator of starvation-induced autophagy in hepatocellular carcinoma (HCC). ASPP2 expression is associated with an autophagic response upon nutrient deprivation and downregulation of ASPP2 facilitates autophagic flux, whereas overexpression of ASPP2 blocks this starvation-induced autophagy in HCC cells. Mechanistically, ASPP2 inhibits autophagy through regulating BECN1 transcription and formation of phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) complex. Firstly, ASPP2 inhibits p65/RelA-induced transcription of BECN1, directly by an ASPP2-p65/RelA-IκBα complex which inhibits phosphorylation of IκBα and the translocation of p65/RelA into the nucleus. Secondly, ASPP2 binds to BECN1, leading to decreased binding of PIK3C3 and UV radiation resistance-associated gene (UVRAG), and increased binding of Rubicon in PIK3C3 complex. Downregulation of ASPP2 enhances the pro-survival and chemoresistant property via autophagy in HCC cells in vitro and in vivo. Decreased ASPP2 expression was associated with increased BECN1 and poor survival in HCC patients. Therefore, ASPP2 is a key regulator of BECN1-dependent autophagy, and decreased ASPP2 may contribute to tumor progression and chemoresistance via promoting autophagy.

Understanding the Effectiveness of Natural Compound Mixtures in Cancer through Their Molecular Mode of Action

“…Another important mechanism of cell death in cancer cells in response to chemotherapy is autophagy, which takes places in the lysosome by self-degrading intracellular proteins and organelles. It triggers cell death in the absence of apoptotic regulators, but in the presence of important autophagy-regulated genes such as BECN1 [7] and ATG5 [8]. In this review, we primarily confine our discussion to apoptotic cell death and autophagic cell death caused by natural chemotherapeutic agents in the context of cancer.…”

DNA damage regulated autophagy modulator 1 recovers the function of apoptosis‑stimulating of p53 protein�2 on inducing apoptotic cell death in Huh7.5 cells

“…We hypothesize that the different background of HCC cell lines is a critical factor that affects the function of ASPP2-induced autophagy on inducing or inhibiting apoptosis. Previous studies demonstrated that ASPP2 is an autophagy inhibitor that impairs the formation of the autophagosome membrane by interacting with Atg5 (10,11). However, a previous study also demonstrated that ASPP2 could induce autophagy development by increasing CHOP expression.…”

Expression and significance of ASPP2 in squamous carcinoma of esophagus

“…In the present study, we demonstrated that ASPP2 expression was significantly decreased in ESCC and was associated with TNM stage, histological differentiation and lymph node As a tumor suppressor and an activator of p53 family, the expression of ASPP2 is often reduced in malignant tumors and it is involved in apoptosis in cancer cells [15,16]. For example, Song B et al analyzed the expression level of ASPP2 in pancreatic cancer tissue samples with qRT-PCR, Western Blot and immunohistochemistry staining.…”

“…As a tumor suppressor and an activator of p53 family, the expression of ASPP2 is often reduced in malignant tumors and it is involved in apoptosis in cancer cells [15,16]. For example, Song B et al.…”