DIRAS3-Derived Peptide Inhibits Autophagy in Ovarian Cancer Cells by Binding to Beclin1

Sutton, Margie N.; Huang, Gary B.; Liang, Xiaowen; Sharma, Rajesh; Reger, Albert S.; Mao, Weiqun; Pang, Lan; Rask, Philip; Lee, Kwangkook; Gray, Joshua P.; Hurwitz, Amy M.; Palzkill, Timothy; Millward, Steven W.; Kim, Choel; Lü, Zhen; Bast, Robert C.

doi:10.3390/cancers11040557

Cited by 17 publications

(14 citation statements)

References 29 publications

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“…Beclin 1 is an important protein involved in the regulation of autophagy (34), which promotes autophagy by localizing to autophagic precursors (35). In the present study, the addition of 2 µM HSYA to Hep-G2 cells significantly increased Beclin 1 protein expression levels at the 6 h time point, indicating that autophagy was induced by regulating Beclin 1 in liver cancer cells.…”

Section: Discussionsupporting

confidence: 57%

Hydroxysafflor yellow�A induces autophagy in human liver cancer cells by regulating Beclin�1 and ERK expression

Chen

Liu

et al. 2020

Exp Ther Med

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Hydroxysafflor yellow A (HSYA) is a water-soluble component of the safflower (Carthamus tinctorius), and research has revealed that HSYA exhibits antitumor effects. In the present study, the effects of HSYA on the autophagy of a Hep-G2 liver cancer cell line, as well as the underlying mechanisms, were investigated. Hep-G2 cells were treated with HSYA and the viability of cells was measured using an MTT assay. Western blotting and immunofluorescence assays were performed to determine the expression of light chain 3 II (LC3-II) and p62, as well as the autophagy regulators Beclin 1 and ERK1/2. Transmission electron microscopy was performed to observe the formation of autophagosomes. The combined effects of HSYA and the autophagy inhibitor chloroquine (CQ) were also determined. The results revealed that the viability of Hep-G2 cells decreased with increasing concentrations of HSYA. Furthermore, LC3-II expression increased significantly and the level of p62 decreased significantly in the HYSA group compared with the control group. Additionally, an increase in Beclin 1 expression and a decrease in phosphorylated-ERK1/2 expression was observed in Hep-G2 cells treated with HYSA. Following treatment with CQ and HSYA, a significant increase in the viability of Hep-G2 cells was observed compared with the HSYA group. Collectively, the results indicated that HSYA induced autophagy by promoting the expression of Beclin 1 and inhibiting the phosphorylation of ERK in liver cancer cells. Therefore, HSYA may serve as a potential therapeutic agent for liver cancer.

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Section: Discussionsupporting

confidence: 57%

Hydroxysafflor yellow�A induces autophagy in human liver cancer cells by regulating Beclin�1 and ERK expression

Chen

Liu

et al. 2020

Exp Ther Med

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“…DIRAS binds to Beclin1 and forms an autophagy initiation complex. DIRAS-derived peptides can bind to Beclin1 and inhibit DIRAS-mediated autophagy [174]. These DIRAS-derived peptides may confer sensitivity to anti-EGFR treatments.…”

Section: Anti-autophagic Peptides That Regulate Response To Anti-ementioning

confidence: 99%

Targeting Autophagy for Overcoming Resistance to Anti-EGFR Treatments

Kwon

Kim

Jung

et al. 2019

Cancers

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Epidermal growth factor receptor (EGFR) plays critical roles in cell proliferation, tumorigenesis, and anti-cancer drug resistance. Overexpression and somatic mutations of EGFR result in enhanced cancer cell survival. Therefore, EGFR can be a target for the development of anti-cancer therapy. Patients with cancers, including non-small cell lung cancers (NSCLC), have been shown to response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR antibodies. However, resistance to these anti-EGFR treatments has developed. Autophagy has emerged as a potential mechanism involved in the acquired resistance to anti-EGFR treatments. Anti-EGFR treatments can induce autophagy and result in resistance to anti-EGFR treatments. Autophagy is a programmed catabolic process stimulated by various stimuli. It promotes cellular survival under these stress conditions. Under normal conditions, EGFR-activated phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling inhibits autophagy while EGFR/rat sarcoma viral oncogene homolog (RAS)/mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) signaling promotes autophagy. Thus, targeting autophagy may overcome resistance to anti-EGFR treatments. Inhibitors targeting autophagy and EGFR signaling have been under development. In this review, we discuss crosstalk between EGFR signaling and autophagy. We also assess whether autophagy inhibition, along with anti-EGFR treatments, might represent a promising approach to overcome resistance to anti-EGFR treatments in various cancers. In addition, we discuss new developments concerning anti-autophagy therapeutics for overcoming resistance to anti-EGFR treatments in various cancers.

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“…Cell-penetrating peptide HIV-TAT(48–57) (GRKKRRQRRR) was fused to peptide FLPNF at the N terminal to enhance cellular permeability, and the TAT linked FLPNF was more effective in inducing autophagy ( Supplementary Figure 1 ). The linker GSG (Gly–Ser–Gly) was added between TAT peptide and peptide FLPNF (GRKKRRQRRR-GSG-FLPNF) to prevent potential interaction between the two peptides and enhance peptide flexibility (Sutton et al, 2019). The synthetic peptides were solubilized in dimethyl sulfoxide (DMSO) at 100 mM according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

“…Autophagosomes are represented by double membrane vesicles. Quantification was performed manually by counting the average number of autophagosomes in 30 randomly selected cells for each group as described previously (Sutton et al, 2019).…”

Section: Methodsmentioning

confidence: 99%

Pentapeptide Protects INS-1 Cells From hIAPP-Mediated Apoptosis by Enhancing Autophagy Through mTOR Pathway

Lin

Jiao

et al. 2019

Front. Pharmacol.

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The human islet amyloid polypeptide (hIAPP), the major component of islet amyloid deposition, is one of the amyloidogenic peptides and has been associated with β cell loss and dysfunction in type 2 diabetes (T2D). Autophagy plays a central role in the clearance of hIAPP aggregates, thereby diminishing the hIAPP-induced cytotoxicity. Conversely, hIAPP has been reported to have interfering effects on the autophagy. The pentapeptide FLPNF developed in our previous study has been shown to have effects on the level of the downstream proteins of mTOR and autophagy–lysosome pathway. In the present study, the peptide FLPNF-mediated increase in autophagy flux and its underlying mechanisms, as well as its protecting effect on INS-1 cells, were investigated. Autophagy flux in INS-1 cells overexpressing hIAPP (hIAPP-INS-1 cells) markedly increased after exposure to peptide FLPNF for 24 h and peaked at a concentration of 200 µM. Peptide FLPNF enhanced the autophagy by inhibiting the mTORC1 activity. Flow cytometry results showed the peptide FLPNF bind to mammalian target of rapamycin (mTOR), and further molecular docking analysis revealed a direct interaction between peptide FLPNF and the FRB domain of mTOR. Meanwhile, both peptide FLPNF and rapamycin significantly decreased the hIAPP-induced apoptosis, whereas 3-MA increased the apoptosis. Furthermore, peptide FLPNF reduced the hIAPP oligomer and improved the hIAPP-INS-1 cells insulin release function at high glucose concentration. Taken together, the peptide FLPNF decreased the hIAPP oligomer via upregulating autophagy by inhibiting mTORC1 activity, thus protecting the INS-1 cells from hIAPP-induced apoptosis and improving the insulin release function of INS-1 cells.

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DIRAS3-Derived Peptide Inhibits Autophagy in Ovarian Cancer Cells by Binding to Beclin1

Cited by 17 publications

References 29 publications

Hydroxysafflor yellow�A induces autophagy in human liver cancer cells by regulating Beclin�1 and ERK expression

Hydroxysafflor yellow�A induces autophagy in human liver cancer cells by regulating Beclin�1 and ERK expression

Targeting Autophagy for Overcoming Resistance to Anti-EGFR Treatments

Pentapeptide Protects INS-1 Cells From hIAPP-Mediated Apoptosis by Enhancing Autophagy Through mTOR Pathway

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