Cinnamaldehyde induces autophagy-mediated cell death through ER stress and epigenetic modification in gastric cancer cells.

Previous reports suggested that cinnamaldehyde (CA), the bioactive ingredient in Cinnamomum cassia, can suppress tumor growth, migratory, and invasive abilities. However, the role and molecular mechanisms of CA in GC are not completely understood. In the present study, we found that CA-induced ER stress and cell death via the PERK-CHOP axis and Ca2+ release in GC cells. Inhibition of ER stress using specific-siRNA blocked CA-induced cell death. Interestingly, CA treatment resulted in autophagic cell death by inducing Beclin-1, ATG5, and LC3B expression and by inhibiting p62 expression whereas autophagy inhibition suppressed CA-induced cell death. We showed that CA induces the inhibition of G9a and the activation of LC3B. Moreover, CA inhibited G9a binding on Beclin-1 and LC3B promoter. Overall, these results suggested that CA regulates the PERK-CHOP signaling, and G9a inhibition activates autophagic cell death via ER stress in GC cells.

Regorafenib induces lethal autophagy arrest by stabilizing PSAT1 in glioblastoma.

GBM (glioblastoma multiforme) is the most common and aggressive brain tumor with no curative options available. Therefore, it is imperative to develop novel potent therapeutic drugs for GBM treatment. Here, we show that regorafenib, an oral multi-kinase inhibitor, exhibits superior therapeutic efficacy over temozolomide, the first-line chemotherapeutic agent for GBM treatment both in vitro and in vivo. Mechanistically, regorafenib directly stabilizes PSAT1 (phosphoserine aminotransferase 1), a critical enzyme for serine synthesis, to trigger PRKAA-dependent autophagy initiation and inhibit RAB11A-mediated autophagosome-lysosome fusion, resulting in lethal autophagy arrest in GBM cells. Maintenance of PSAT1 at a high level is essential for regorafenib-induced GBM suppression. Together, our data provide novel mechanistic insights of regorafenib-induced autophagy arrest and suggest a new paradigm for effective treatment of GBM.Abbreviations: 3-MA: 3-methyladenine; ACACA: acetyl coenzyme A carboxylase alpha; ACTB/ß-actin: actin, beta; AMPK: adenosine monophosphate-activated protein kinase; ATG5: autophagy related 5; CTSD: cathepsin D; DN-: dominant-negative; GBM: glioblastoma multiforme; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PSAT1: phosphoserine aminotransferase 1; SQSTM1/p62: sequestosome 1; TKIs: tyrosine kinase inhibitors.

Autophagy involved in antiviral activity of sodium tanshinone IIA sulfonate against porcine reproductive and respiratory syndrome virus infection in vitro.

BACKGROUND: In previous research, we have demonstrated that sodium tanshinone IIA sulfonate (STS) has anti-porcine reproductive and respiratory syndrome virus (PRRSV) activity, but whether autophagy is involved in this process is still unknown. In this study, the autophagy effect of STS against PRRSV infection was investigated in vitro. METHODS: Quantitative real-time PCR (qRT-PCR) and western blot was used to evaluate the inhibition ability of STS on the mRNA expression levels on cell autophagy genes, that is Beclin1, ATG5 and ATG7. Simultaneously, the effect of STS on N protein/gene expression was assessed by indirect immuno-fluorescence assay (IFA), qRT-PCR and western blot. RESULTS: The results indicated that STS inhibits autophagy induced by PRRSV. In addition, STS effectively suppresses PRRSV's N protein replication and N gene expression in Marc-145 cells infected with PRRSV in a time-dependent manner. CONCLUSIONS: Our results suggest that STS exhibits anti-PRRSV activity in vitro by suppressing autophagy-related genes, which may provide a theoretical basis for further pharmacological agent development regarding PRRSV infection.

Schisandrin C enhances odontoblastic differentiation through autophagy and mitochondrial biogenesis in human dental pulp cells.

OBJECTIVE: To investigate the role of Schisandrin C in odontoblastic differentiation, and its relations between autophagy and mitochondrial biogenesis in human dental pulp cells (HPDCs). DESIGN: Fresh third molars were used, and cultured for HDPCs. Western blotting technique, Alizarin red S staining, alkaline phosphatase (ALP) activity, and confocal microscopy were used to detect autophagy, mitochondrial biogenesis, and odontoblastic differentiation. To understand the mechanism of Schisandrin C, the HDPCs were treated with lipopolysaccharide (LPS), autophagy and heme oxygenase-1 (HO-1) inhibitors: 3-Methyladenine (3-MA) and Zinc protoporphyrin IX (ZnPP), respectively. RESULTS: LPS decreased the expression of autophagy molecules [autophagy protein 5 (ATG-5), beclin-1, and microtubule-associated protein 1A/1B light chain 3 (LC3-I/II)] and mitochondrial biogenesis molecules [heme oxygenase-1 (HO-1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)], and disrupted odontoblastic differentiation. The down-regulation of autophagy and mitochondrial biogenesis with 3-MA and ZnPP inhibited odontoblastic differentiation. However, Schisandrin C restored the expression of all the above molecules, even with LPS and inhibitor treatment. This result demonstrates that autophagy and mitochondrial biogenesis plays an essential role in odontoblastic differentiation, and Schisandrin C activates these systems to promote odontoblastic differentiation of HDPCs. CONCLUSION: Schisandrin C has potential characters to regulate odontoblastic differentiation, and may be recommended for use as a compound for pulp homeostasis.

Protein kinase C ß inhibits autophagy and sensitizes cervical cancer Hela cells to cisplatin.

Recently, autophagy has been indicated to play an essential role in various biological events, such as the response of cervical cancer cells to chemotherapy. However, the exact signalling mechanism that regulates autophagy during chemotherapy remains unclear. In the present study, we investigated the regulation by cisplatin on protein kinase C ß (PKC ß), on B-cell lymphoma 2 (Bcl-2) and on apoptosis in cervical cancer Hela cells. And then we examined the regulation by cisplatin on autophagy and the role of autophagy on the chemotherapy in Hela cells. In addition, the regulation of the PKC ß on the autophagy was also investigated. Our results indicated that cisplatin promoted PKC ß in Hela cells. The PKC ß inhibitor reduced the cisplatin-induced apoptosis, whereas increased the cisplatin-induced autophagy in Hela cells. On the other side, the PKC ß overexpression aggravated the cisplatin-induced apoptosis, whereas down-regulated the cisplatin-induced autophagy. Taken together, our study firstly recognized the involvement of PKC ß in the cytotoxicity of cisplatin via inhibiting autophagy in cervical cancer cells. We propose that PKC ß would sensitize cervical cancer cells to chemotherapy via reducing the chemotherapy induced autophagy in cancer cells.