Inhibition of SIRT1/2 upregulates HSPA5 acetylation and induces pro-survival autophagy via ATF4-DDIT4-mTORC1 axis in human lung cancer cells

AbstractSirtuins have emerged as a promising novel class of anti-cancer drug targets. Inhibition of SIRT1 and SIRT2 induces apoptosis in cancer cells and they play multifaceted roles in regulating autophagy. In the present study, we found that salermide, a SIRT1/2-specific inhibitor or small interfering RNAs (siRNAs) to block SIRT1/2 expression could induce autophagy in human NSCLC cells. Moreover, SIRT1/2 inhibition increased the expression levels of ATF4 and DDIT4 and downregulated p-RPS6KB1 and p-EIF4EBP1, two downstream molecules of mTORC1. Moreover, ATF4 or DDIT4 knockdown attenuated salermide-induced autophagy, suggesting that SIRT1/2 inhibition induced autophagy through the ATF4-DDIT4-mTORC1 axis. Mechanistically, SIRT1/2 inhibition led to HSPA5 acetylation and dissociation from EIF2AK3, leading to ER stress response and followed by upregulation of ATF4 and DDIT4, triggering autophagy. Silencing of the autophagic geneATG5 in lung cancer cells resulted in increased apoptotic cell death induced by SIRT1/2 inhibition. Our data show that inhibition of SIRT1/2 induces pro-survival autophagy via acetylation of HSPA5 and subsequent activation of ATF4 and DDIT4 to inhibit the mTOR signaling pathway in NSCLC cells. These findings suggest that combinatorial treatment with SIRT1/2 inhibitors and pharmacological autophagy inhibitors is an effective therapeutic strategy for cancer therapy.
Source: Apoptosis - Category: Molecular Biology Source Type: research

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Crizotinib is a tyrosine kinase inhibitor that has been found to be effective in the treatment of anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer. This targeted cancer therapy agent has been shown to have superior efficacy over standard chemotherapy in this small subset of lung cancer patients. An adverse effect of this drug therapy is the development of complex renal cysts. Here, we present a case of a 68-year-old patient with non-small cell lung cancer on Crizotinib therapy who developed complex bilateral renal cysts.
Source: Clinical Imaging - Category: Radiology Authors: Tags: Body Imaging Source Type: research
In conclusion, or data indicates that multiple different adaptive mechanisms may act in concert to blunt the cellular impact of EGFR inhibition, and we suggest BCL6 as a potential target for EGFR inhibitor-based combination therapy. PMID: 32234966 [PubMed - as supplied by publisher]
Source: Molecular and Cellular Proteomics : MCP - Category: Molecular Biology Authors: Tags: Mol Cell Proteomics Source Type: research
(St. Michael's Hospital) A medication commonly used to treat non-small cell lung cancer that has spread, or metastasized, may have benefits for patients with metastatic brain cancers, suggests a new review and analysis led by researchers at St. Michael's Hospital of Unity Health Toronto and Harvard Medical School.
Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news
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Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news
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Source: Cancer Biomarkers : Section A of Disease Markers - Category: Cancer & Oncology Authors: Tags: Cancer Biomark Source Type: research
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Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
Immune checkpoint inhibitors (ICIs) are emerging as a new treatment option for cancer therapy[1]. Unlike conventional cytotoxic chemotherapy, ICI does not cause cancer cell death directly, but rather alters cancer immunity and the tumor microenvironment [1 –4]. With the increasingly widespread use of ICIs, an issue has emerged; namely, that conventional response criteria based on tumor size may not be adequate for evaluating anti-tumor activity and long-term efficacy of ICIs [5,6]. Compared with chemotherapy, ICIs achieve modest or sometimes no sign ificant improvement in tumor response as assessed according to the R...
Source: Lung Cancer - Category: Cancer & Oncology Authors: Source Type: research
Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. Most lung cancer patients are diagnosed at advanced stages and may benefit from pembrolizumab (anti-PD-1 antibody), cytotoxic chemotherapy and other adjuvant therapies. Despite the availability of various therapies, the response and survival rates have been low. Therefore, study of different targets for the treatment of lung cancer has been one of the major focuses of cancer research. The ubiquitin proteasome system (UPS) is a crucial regulator of cell homeostasis and plays an essential role in growth and development of all cells. The UP...
Source: Current Cancer Drug Targets - Category: Cancer & Oncology Authors: Tags: Curr Cancer Drug Targets Source Type: research
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Source: Biomedicine and Pharmacotherapy - Category: Drugs & Pharmacology Source Type: research
In this study, we attempted to fabricate Nitroimidazoles (NI) and Hyaluronic acid (HA) co-decorated, cisplatin (DDP) loaded polymeric nanoparticles (PNPs) (NI/HA-DDP-PNPs) and lipid-polymer hybrid nanoparticles (LPNs) (NI/HA-DDP-LPNs) for the facilitated drug delivery at lung tumor regions (hypoxic regions). In vitro cytotoxicity and cellular uptake; In vivo anti-tumor activity and in vivo tissue biodistribution of PNPs and LPNs were evaluated and compared in lung carcinoma cells and xenograft. Hydrodynamic size of NI/HA-DDP-LPNs was 185.6 ± 4.7 nm, which is larger than that of NI/HA-DDP-PNPs (136.7 ± 3.5 nm)...
Source: Biomedicine and pharmacotherapy = Biomedecine and pharmacotherapie - Category: Drugs & Pharmacology Authors: Tags: Biomed Pharmacother Source Type: research
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