Autophagy as a molecular target for cancer treatment

Kocatürk, Nur Mehpare; Akkoç, Yunus; Kığ, Cenk; Bayraktar, Öznur; Gözüaçık, Devrim; Kutlu, Özlem

doi:10.1016/j.ejps.2019.04.011

Cited by 263 publications

(187 citation statements)

References 346 publications

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“…Autophagy is an important component in cellular activity in which cytoplasmic materials are directly degraded by lysosomes (32). Cancer cells bene t from exploiting autophagy in stressful conditions such as nutrient deprivation, hypoxia and oxidative stress, but excessive autophagy activities also lead to cell death (33).…”

Section: Discussionmentioning

confidence: 99%

Pegylated recombinant human arginase 1 induces autophagy and apoptosis via the ROS-activated AKT/mTOR pathway in bladder cancer cells

Zhao¹,

Zhang

Li³

et al. 2020

Preprint

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Background Bladder cancer is one of the dominant cancers worldwide, especially for male. Currently, the therapeutical regimen of bladder cancer is based on surgery, radiation therapy, chemotherapy and immunotherapy, but the clinical outcome is still needed to improve. Recombinant human arginase (rhArg, BCT-100) is a novel agent to show great anticancer effect on arginine auxotrophic tumor. However, the effect of rhArg on bladder cancer still remains unclear. Methods A panel of six bladder cancer cell lines (BIU-87, EJ-1, J82, SCaBER, T24 and 5637) was employed to assess the anticancer effect of BCT-100 in vitro by MTT assay. T24 nude mice xenograft models were established to evaluate the anticancer effect of BCT-100 in vivo. Protein level (argininosuccinate synthetase 1 (ASS1), ornithine transcarbamylase, cleaved-PARP, PEG, Survivin, p62, Beclin-1, LC3B, p-AKT, p-mTOR) was detected by Western blot. Intracellular, serum and intratumoral arginine concentrations were examined by ELISA. Apoptotic rate, H2O2 and mitochondrial membrane depolarization were tested by flow cytometer. Immunoflorescence on ki67 and TUNEL assay were applied to identify cellular and tumoral apoptotic events. Results BCT-100 displayed anticancer effects on bladder cancer cells in vitro and in vivo. The expression of ASS1 varies in different bladder cancer cell lines, and ornithine transcarbamylase is almost deficient except weakly expressed in SCaBER cell line. Knockdown ASS1 in BIU-87 cells could enhance the cytotoxicity induced by BCT-100. Intracellular arginine level was sharply decreased followed by apoptotic events. Futhermore, BCT-100 induced H2O2 production and mitochondrial membrane depolarization, leading to cytochrome c and smac released from mitochondria to cytosol. The expression of LC3B and Becllin-1 was up-regulated, while p62 was down-regulated in a time dependent manner. Autophagic flux was also observed upon BCT-100 treatment. Besides, the phosphorylation of AKT/mTOR pathway was suppressed in a time dependent fashion in BCT-100-treated T24 cells. N-Acetyl-L-cystein reduced the apoptosis and autophagy induced by BCT-100, while CQ, MK-2206 and rapamycin potentiated the apoptosis triggered by BCT-100. Conclusions The present study demonstrated that BCT-100 induced autophagy and apoptosis via ROS mediated AKT/mTOR signaling pathway in bladder cancer cells.

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Section: Discussionmentioning

confidence: 99%

Pegylated recombinant human arginase 1 induces autophagy and apoptosis via the ROS-activated AKT/mTOR pathway in bladder cancer cells

Zhao¹,

Zhang

Li³

et al. 2020

Preprint

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“…On the one hand, autophagy provides necessary nutrition and energy to promote tumor survival under physiological or pathological conditions, such as nutrient deficiency, hypoxia, ER stress, protein misfolding and aggregation, and metabolic stress, etc. ( 36 , 37 ). Additionally, therapeutic agents, such as radiotherapy and chemotherapy, overinduce protective autophagy in cancer cells, leading to cell desensitization and eventually development of resistance to therapy.…”

Section: The Role Of Autophagy In Glioblastoma Therapy With the Phospmentioning

confidence: 99%

“…In addition, bafilomycin A1 induces the binding of BECN1 to Bcl-2 (apoptosis regulator), which reduces functional autophagy and promotes apoptotic cell death ( 95 ). The PI3K inhibitors 3MA ( 96 ), wortmannin, and LY294002 have also been used as autophagy inhibitors based on their inhibitory effect on PIK3C3 activity, which is essential for induction of autophagy ( 37 ). Lys05 is a newly synthetic lysosomotropic agent that has anti-glioma activity by inducing lysosomal membrane permeabilization and inhibition of autophagy, resulting in decreased cell viability and cell growth, as well as radiosensitivity of glioma U251 and LN229 cells ( 97 ).…”

Section: Prospect-targeting Autophagy In Glioblastoma Therapymentioning

confidence: 99%

Therapeutic Potential of Autophagy in Glioblastoma Treatment With Phosphoinositide 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin Signaling Pathway Inhibitors

Qin

Zhang

et al. 2020

Front. Oncol.

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Glioblastoma (GB) is the most malignant and aggressive form of brain tumor, characterized by frequent hyperactivation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. PI3K/AKT/mTOR inhibitors have a promising clinical efficacy theoretically. However, strong drug resistance is developed in GB against the PI3K/AKT/mTOR inhibitors due to the cytoprotective effect and the adaptive response of autophagy during the treatment of GB. Activation of autophagy by the PI3K/AKT/mTOR inhibitors not only enhances treatment sensitivity but also leads to cell survival when drug resistance develops in cancer cells. In this review, we analyze how to increase the antitumor effect of the PI3K/AKT/mTOR inhibitors in GB treatment, which is achieved by various mechanisms, among which targeting autophagy is an important mechanism. We review the dual role of autophagy in both GB therapy and resistance against inhibitors of the PI3K/AKT/mTOR signaling pathway, and further discuss the possibility of using combinations of autophagy and PI3K/AKT/mTOR inhibitors to improve the treatment efficacy for GB. Finally, we provide new perspectives for targeting autophagy in GB therapy.

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“…Probably due to the dual role of autophagy in cancer, both as an inhibitor and as an activator, there is an increasing interest to investigate the modulation of autophagy as a potential avenue for cancer therapy. The application of pharmacological modulators of autophagy has shown promise in some in vitro and in vivo studies, but not in others [56][57][58]. Several studies have reported that treatment with anti-cancer drugs resulted in the induction of autophagy in a range of cancer cell lines [59].…”

Section: Autophagy a Potential Target For Cancer Treatmentmentioning

confidence: 99%

Regulation of Autophagy Is a Novel Tumorigenesis-Related Activity of Multifunctional Translationally Controlled Tumor Protein

Lee¹,

Jang²,

Woo³

et al. 2020

Cells

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Translationally controlled tumor protein (TCTP) is highly conserved in eukaryotic organisms and plays multiple roles regulating cellular growth and homeostasis. Because of its anti-apoptotic activity and its role in the regulation of cancer metastasis, TCTP has become a promising target for cancer therapy. Moreover, growing evidence points to its clinical role in cancer prognosis. How TCTP regulates cellular growth in cancer has been widely studied, but how it regulates cellular homeostasis has received relatively little attention. This review discusses how TCTP is related to cancer and its potential as a target in cancer therapeutics, including its novel role in the regulation of autophagy. Regulation of autophagy is essential for cell recycling and scavenging cellular materials to sustain cell survival under the metabolic stress that cancer cells undergo during their aggressive proliferation.

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Autophagy as a molecular target for cancer treatment

Cited by 263 publications

References 346 publications

Pegylated recombinant human arginase 1 induces autophagy and apoptosis via the ROS-activated AKT/mTOR pathway in bladder cancer cells

Pegylated recombinant human arginase 1 induces autophagy and apoptosis via the ROS-activated AKT/mTOR pathway in bladder cancer cells

Therapeutic Potential of Autophagy in Glioblastoma Treatment With Phosphoinositide 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin Signaling Pathway Inhibitors

Regulation of Autophagy Is a Novel Tumorigenesis-Related Activity of Multifunctional Translationally Controlled Tumor Protein

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