Autophagy is a highly conserved catabolic process induced under various conditions of cellular stress, which prevents cell damage and promotes survival in the event of energy or nutrient shortage and responds to various cytotoxic insults. Thus, autophagy has primarily cytoprotective functions and needs to be tightly regulated to respond correctly to the different stimuli that cells experience, thereby conferring adaptation to the ever-changing environment. It is now apparent that autophagy is deregulated in the context of various human pathologies, including cancer and neurodegeneration, and its modulation has considerable potential as a therapeutic approach.

Mechanism and medical implications of mammalian autophagy

Induction of cell death and inhibition of cell survival are the main principles of cancer therapy. Resistance to chemotherapeutic agents is a major problem in oncology, which limits the effectiveness of anticancer drugs. A variety of factors contribute to drug resistance, including host factors, specific genetic or epigenetic alterations in the cancer cells and so on. Although various mechanisms by which cancer cells become resistant to anticancer drugs in the microenvironment have been well elucidated, how to circumvent this resistance to improve anticancer efficacy remains to be defined. Autophagy, an important homeostatic cellular recycling mechanism, is now emerging as a crucial player in response to metabolic and therapeutic stresses, which attempts to maintain/restore metabolic homeostasis through the catabolic lysis of excessive or unnecessary proteins and injured or aged organelles. Recently, several studies have shown that autophagy constitutes a potential target for cancer therapy and the induction of autophagy in response to therapeutics can be viewed as having a prodeath or a prosurvival role, which contributes to the anticancer efficacy of these drugs as well as drug resistance. Thus, understanding the novel function of autophagy may allow us to develop a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in the treatment of cancer patients.

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Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment

In many solid tumor types, tumor-associated macrophages (TAMs) are important components of the tumor microenvironment (TME). Moreover, TAMs infiltration is strongly associated with poor survival in solid tumor patients. In this review, we describe the origins of TAMs and their polarization state dictated by the TME. We also specifically focus on the role of TAMs in promoting tumor growth, enhancing cancer cells resistance to chemotherapy and radiotherapy, promoting tumor angiogenesis, inducing tumor migration and invasion and metastasis, activating immunosuppression. In addition, we discuss TAMs can be used as therapeutic targets of solid tumor in clinics. The therapeutic strategies include clearing macrophages and inhibiting the activation of TAMs, promoting macrophage phagocytic activity, limiting monocyte recruitment and other targeted TAMs therapies.

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Tumor-associated macrophages: an accomplice in solid tumor progression

Reactive oxygen species (ROS), a group of ions and molecules, include hydroxyl radicals (·OH), alkoxyl radicals, superoxide anion (O2·−), singlet oxygen (1O2) and hydrogen peroxide (H2O2). Hydroxyl radicals and alkoxyl radicals are extremely and highly reactive species respectively. Endogenous ROS are mainly formed in mitochondrial respiratory chain. Low levels of ROS play important roles in regulating biological functions in mammalian cells. However, excess production of ROS can induce cell death by oxidative damaging effects to intracellular biomacromolecules. Cancer cell death types induced by ROS include apoptotic, autophagic, ferroptotic and necrotic cell death. Since abnormal metabolism in cancer cells, they have higher ROS content compared to normal cells. The higher endogenous ROS levels in cancer cells endow them more susceptible to the ROS-induction treatment. Indeed, some anticancer drugs currently used in clinic, such as molecular targeted drugs and chemotherapeutic agents, effectively kill cancer cells by inducing ROS generation. In addition, photodynamic therapy (PDT) is mainly based on induction of ROS burst to kill cancer cells. The mechanism of cell death induced by radiotherapy using ionizing radiation also refers to ROS production. Moreover, ROS play an important role in tumor immune therapy. Altogether, combining above traditional treatments with ROS-induced agents will be considered as a promising strategy in cancer therapy. In this review, we focus on our current understanding of the anticancer effects of ROS.

Induction of reactive oxygen species: an emerging approach for cancer therapy.

// Anqun Tang 1,* , Keyu Gao 1,* , Laili Chu 1,* , Rui Zhang 1 , Jing Yang 1 and Junnian Zheng 1,2 1 Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Jiangsu, China 2 Department of Oncology, The First Affiliated Hospital, Xuzhou Medical University, Xuzhou, Jiangsu, China * These authors have contributed equally to this work Correspondence to: Junnian Zheng, email: // Jing Yang, email: // Keywords : Aurora kinases, mitosis, cancer therapy target, Aurora kinases inhibitors, combination therapy Received : November 01, 2016 Accepted : January 17, 2017 Published : January 29, 2017 Abstract Aurora kinases, a family of serine/threonine kinases, consisting of Aurora A (AURKA), Aurora B (AURKB) and Aurora C (AURKC), are essential kinases for cell division via regulating mitosis especially the process of chromosomal segregation. Besides regulating mitosis, Aurora kinases have been implicated in regulating meiosis. The deletion of Aurora kinases could lead to failure of cell division and impair the embryonic development. Overexpression or gene amplification of Aurora kinases has been clarified in a number of cancers. And a growing number of studies have demonstrated that inhibition of Aurora kinases could potentiate the effect of chemotherapies. For the past decades, a series of Aurora kinases inhibitors (AKIs) developed effectively repress the progression and growth of many cancers both in vivo and in vitro , suggesting that Aurora kinases could be a novel therapeutic target. In this review, we’ll first briefly present the structure, localization and physiological functions of Aurora kinases in mitosis, then describe the oncogenic role of Aurora kinases in tumorigenesis, we shall finally discuss the outcomes of AKIs combination with conventional therapy.

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Aurora kinases: novel therapy targets in cancers

We have previously shown that elevated expression of mitotic kinase aurora kinase A (AURKA) in cancer cells promotes the development of metastatic phenotypes and is associated clinically with adverse prognosis. Here, we first revealed a clinically positive correlation between AURKA and autophagy-associated protein SQSTM1 in breast cancer and further demonstrated that AURKA regulated SQSTM1 through autophagy. Indeed, depletion by siRNA or chemical inhibition of AURKA by the small molecule VX-680 increased both the level of microtubule-associated protein 1 light chain 3-II (LC3-II) and the number of autophagosomes, along with decreased SQSTM1. Conversely, overexpression of AURKA inhibited autophagy, as assessed by decreased LC3-II and increased SQSTM1 either upon nutrient deprivation or normal conditions. In addition, phosphorylated forms of both RPS6KB1 and mechanistic target of rapamycin (MTOR) were elevated by overexpression of AURKA whereas they were suppressed by depletion or inhibition of AURKA. Moreover, inhibition of MTOR by PP242, an inhibitor of MTOR complex1/2, abrogated the changes in both LC3-II and SQSTM1 in AURKA-overexpressing BT-549 cells, suggesting that AURKA-suppressed autophagy might be associated with MTOR activation. Lastly, repression of autophagy by depletion of either LC3 or ATG5, sensitized breast cancer cells to VX-680-induced apoptosis. Similar findings were observed in cells treated with the autophagy inhibitors chloroquine (CQ) and bafilomycin A 1 (BAF). Our data thus revealed a novel role of AURKA as a negative regulator of autophagy, showing that AURKA inhibition induced autophagy, which may represent a novel mechanism of drug resistance in apoptosis-aimed therapy for breast cancer.

Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells

Background The aim of the current study is to investigate the change in anxiety and depression amongst Chinese breast cancer patients and to identify causal associations between baseline variables and the trajectory of anxiety and depression within this identified group. Methods This is a longitudinal prospective study. Three hundred women with breast cancer were recruited. Patient's depression and anxiety were repeatedly measured by PHQ-9 and GAD-7 at baseline, 6, 12, and 18 months after discharge. The SAS 9.4 PROC Traj procedure was used to examine the group-based trajectory of these recruited patients. Linear mixed models (LMM) were utilized to examine anxiety/depression changes over time, accounting for relevant baseline demographic and clinical factors. Results About 26.3% of the participants reported none or very mild anxiety over time, 60.7% reported stable low-level anxiety, and the remaining 13.0% showed significantly decreasing trend in GAD total scores. Meanwhile, 10.7% of the participants reported none or very mild depressive symptoms over time, 66.0% reported stable PHQ total scores throughout the research period, and 23.3% were classified as the “high level-decreasing group”. Patients reported significantly higher anxiety and depression scores in the first three assessments. Participants with no or mild life stress along with a positive personality tended to report lower anxiety and depression scores over time. Conclusion Most of the breast cancer patients reported stable low-level anxiety and depression 18 months after discharge. Early assessment of optimism and stress levels among cancer patients might help identify people at risk of experiencing long-term anxiety and depression.

Qiongxia Zhang

Papers

Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells

Group-based trajectory and predictors of anxiety and depression among Chinese breast cancer patients