https://www.cell.com/trends/biochemical-sciences/pdf/S0968-0004(10)00140-4.pdf

Regulation of autophagy by ROS: physiology and pathology

Autophagy is a conserved, self-degradation system that is critical for maintaining cellular homeostasis during stress conditions. Dysregulated autophagy has implications in health and disease. Specifically, in cancer, autophagy plays a dichotomous role by inhibiting tumor initiation but supporting tumor progression. Early results from clinical trials that repurposed hydroxychloroquine for cancer have suggested that autophagy inhibition may be a promising approach for advanced cancers. In this review of the literature, the authors present fundamental advances in the biology of autophagy, approaches to targeting autophagy, the preclinical rationale and clinical experience with hydroxychloroquine in cancer clinical trials, the potential role of autophagy in tumor immunity, and recent developments in next-generation autophagy inhibitors that have clinical potential. Autophagy is a promising target for drug development in cancer. Cancer 2018. © 2018 American Cancer Society.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.31335

Targeting autophagy in cancer

Reactive oxygen species (ROS) and antioxidant ingredients are a series of crucial signaling molecules in oxidative stress response. Under some pathological conditions such as traumatic brain injury, ischemia/reperfusion, and hypoxia in tumor, the relative excessive accumulation of ROS could break cellular homeostasis, resulting in oxidative stress and mitochondrial dysfunction. Meanwhile, autophagy is also induced. In this process, oxidative stress could promote the formation of autophagy. Autophagy, in turn, may contribute to reduce oxidative damages by engulfing and degradating oxidized substance. This short review summarizes these interactions between ROS and autophagy in related pathological conditions referred to as above with a focus on discussing internal regulatory mechanisms. The tight interactions between ROS and autophagy reflected in two aspects: the induction of autophagy by oxidative stress and the reduction of ROS by autophagy. The internal regulatory mechanisms of autophagy by ROS can be summarized as transcriptional and post-transcriptional regulation, which includes various molecular signal pathways such as ROS–FOXO3–LC3/BNIP3–autophagy, ROS–NRF2–P62–autophagy, ROS–HIF1–BNIP3/NIX–autophagy, and ROS–TIGAR–autophagy. Autophagy also may regulate ROS levels through several pathways such as chaperone-mediated autophagy pathway, mitophagy pathway, and P62 delivery pathway, which might provide a further theoretical basis for the pathogenesis of the related diseases and still need further research.

ROS and Autophagy: Interactions and Molecular Regulatory Mechanisms

https://www.gastrojournal.org/article/S0016-5085(10)01104-2/pdf

Autophagy Reduces Acute Ethanol-Induced Hepatotoxicity and Steatosis in Mice

Autophagy is the process by which cellular material is delivered to lysosomes for degradation and recycling. There are three different types of autophagy, but macroautophagy, which involves the formation of double membrane vesicles that engulf proteins and organelles that fuse with lysosomes, is by far the most studied and is thought to have important context-dependent roles in cancer development, progression, and treatment. The roles of autophagy in cancer treatment are complicated by two important discoveries over the past few years. First, most (perhaps all) anticancer drugs, as well as ionizing radiation, affect autophagy. In most, but not all cases, these treatments increase autophagy in tumor cells. Second, autophagy affects the ability of tumor cells to die after drug treatment, but the effect of autophagy may be to promote or inhibit cell death, depending on context. Here we discuss recent research related to autophagy and cancer therapy with a focus on how these processes may be manipulated to improve cancer therapy.

https://molpharm.aspetjournals.org/content/molpharm/early/2014/02/26/mol.114.091850.full.pdf

Autophagy and Cancer Therapy

Oxidative stress induces parallel autophagy and mitochondria dysfunction in human glioma U251 cells

This report describes an integrated study on identification of potential markers for gastric cancer in patients’ cancer tissues and sera based on: (i) genome-scale transcriptomic analyses of 80 paired gastric cancer/reference tissues and (ii) computational prediction of blood-secretory proteins supported by experimental validation. Our findings show that: (i) 715 and 150 genes exhibit significantly differential expressions in all cancers and early-stage cancers versus reference tissues, respectively; and a substantial percentage of the alteration is found to be influenced by age and/or by gender; (ii) 21 co-expressed gene clusters have been identified, some of which are specific to certain subtypes or stages of the cancer; (iii) the top-ranked gene signatures give better than 94% classification accuracy between cancer and the reference tissues, some of which are gender-specific; and (iv) 136 of the differentially expressed genes were predicted to have their proteins secreted into blood, 81 of which were detected experimentally in the sera of 13 validation samples and 29 found to have differential abundances in the sera of cancer patients versus controls. Overall, the novel information obtained in this study has led to identification of promising diagnostic markers for gastric cancer and can benefit further analyses of the key (early) abnormalities during its development.

An integrated transcriptomic and computational analysis for biomarker identification in gastric cancer

/pdf/an-integrated-transcriptomic-and-computationalanalysis-for-164s54uavq.pdf

An integrated transcriptomic and computationalanalysis for biomarker identification ingastric cancer

Inhibition of autophagy enhances cisplatin cytotoxicity through endoplasmic reticulum stress in human cervical cancer cells

The mechanisms underlying cisplatin resistance in tumors are not fully understood. Previous studies have reported that cellular resistance to oxidative stress is accompanied by resistance to cisplatin. However, the relationship between the resistance to oxidative stress and cisplatin drug resistance in human ovarian cancer cells (HOCCs) is not clear. Here, we reveal a critical role for the multifunctional protein p62/SQSTM1 in cisplatin resistance in human ovarian cancer cells (HOCCs). p62/SQSTM1 (sequestosome 1) plays important roles in cell differentiation, proliferation and as an antiapoptotic molecule. We found that cisplatin-resistant SKOV3/DDP cells express much higher levels of p62 than do cisplatin-sensitive SKOV3 cells. The protein p62 can activate the Keap1-Nrf2-ARE signaling pathway and induce the expression of antioxidant genes in SKOV3/DDP cells. Knockdown of p62 resensitizes SKOV3/DDP cells to cisplatin. Collectively, our data indicate that cisplatin resistance in HOCCs is partially attributable to their high expression of p62, which plays an important role in preventing ROS stress-induced apoptosis by regulating the Keap1-Nrf2-ARE signaling pathway.

https://www.spandidos-publications.com/10.3892/ijo.2014.2669/download

Jinsong Kang

Papers

Oxidative stress induces parallel autophagy and mitochondria dysfunction in human glioma U251 cells

An integrated transcriptomic and computational analysis for biomarker identification in gastric cancer

An integrated transcriptomic and computationalanalysis for biomarker identification ingastric cancer

Inhibition of autophagy enhances cisplatin cytotoxicity through endoplasmic reticulum stress in human cervical cancer cells

p62/SQSTM1 is involved in cisplatin resistance in human ovarian cancer cells via the Keap1-Nrf2-ARE system