logo logo
High Glucose Accelerates Tumor Progression by Regulating MEDAG-Mediated Autophagy Levels in Breast Cancer. International journal of biological sciences Recent studies have shown that diabetes is a major risk factor for breast cancer (BC), but the mechanism is incompletely understood. Mesenteric estrogen-dependent adipogenesis (MEDAG) plays a significant role in both glucose uptake and BC development. However, the relationship between MEDAG and BC under high glucose (HG) conditions remains unclear. In our study, MEDAG expression was higher in BC tissue from diabetic patients than in BC tissue from nondiabetic patients. HG promoted BC progression and by upregulating MEDAG expression. Furthermore, MEDAG deficiency increased the autophagosome number and autophagic flux. Moreover, inhibition of autophagy partially reversed MEDAG knockdown (MEDAG)-induced suppression of tumorigenic biological behaviors and epithelial-mesenchymal transition (EMT) progression. Finally, MEDAG significantly suppressed AMPK phosphorylation. Additionally, the AMPK inhibitor Compound C markedly reduced autophagosome accumulation and antitumor effects in MEDAG cells. Treatment with the AMPK activator AICAR exhibited similar effects in MEDAG-overexpressing (MEDAG) cells. In conclusion, the MEDAG-AMPK-autophagy axis is vital to BC progression in diabetic patients. Our findings provide a novel treatment target for BC in patients with diabetes. 10.7150/ijbs.70002
Eugenol-Induced Autophagy and Apoptosis in Breast Cancer Cells via PI3K/AKT/FOXO3a Pathway Inhibition. Abdullah Mashan L,Al-Shabanah Othman,Hassan Zeinab K,Hafez Mohamed M International journal of molecular sciences The use of natural compounds is promising in approaches to prevent and treat cancer. The long-term application of most currently employed chemotherapy techniques has toxic side effects. Eugenol, a phenolic phytochemical extracted from certain essential oils, has an anti-cancer effect. The modulation of autophagy can promote either the survival or apoptosis of cancer cells. Triple-negative (MDA-MB-231) and HER2 positive (SK-BR-3) breast cancer cell lines were treated with different doses of eugenol. Apoptosis was detected by a flow-cytometry technique, while autophagy was detected by acridine orange. Real-time PCR and Western blot assays were applied to investigate the effect of eugenol on the gene and protein expression levels of autophagy and apoptotic genes. Treating cells with different concentrations of eugenol significantly inhibited cell proliferation. The protein levels of AKT serine/threonine kinase 1 (AKT), forkhead box O3 (FOXO3a), cyclin dependent kinase inhibitor 1A (p21), cyclin-dependent kinase inhibitor (p27), and Caspase-3 and -9 increased significantly in Eugenol-treated cells. Eugenol also induced autophagy by upregulating the expression levels of microtubule-associated protein 1 light chain 3 (LC3) and downregulating the expression of nucleoporin 62 (NU p62). Eugenol is a promising natural anti-cancer agent against triple-negative and HER2-positive breast cancer. It appears to work by targeting the caspase pathway and by inducing autophagic cell death. 10.3390/ijms22179243
Autophagy and autophagy-related proteins in cancer. Li Xiaohua,He Shikun,Ma Binyun Molecular cancer Autophagy, as a type II programmed cell death, plays crucial roles with autophagy-related (ATG) proteins in cancer. Up to now, the dual role of autophagy both in cancer progression and inhibition remains controversial, in which the numerous ATG proteins and their core complexes including ULK1/2 kinase core complex, autophagy-specific class III PI3K complex, ATG9A trafficking system, ATG12 and LC3 ubiquitin-like conjugation systems, give multiple activities of autophagy pathway and are involved in autophagy initiation, nucleation, elongation, maturation, fusion and degradation. Autophagy plays a dynamic tumor-suppressive or tumor-promoting role in different contexts and stages of cancer development. In the early tumorigenesis, autophagy, as a survival pathway and quality-control mechanism, prevents tumor initiation and suppresses cancer progression. Once the tumors progress to late stage and are established and subjected to the environmental stresses, autophagy, as a dynamic degradation and recycling system, contributes to the survival and growth of the established tumors and promotes aggressiveness of the cancers by facilitating metastasis. This indicates that regulation of autophagy can be used as effective interventional strategies for cancer therapy. 10.1186/s12943-020-1138-4
Flubendazole elicits anti-cancer effects via targeting EVA1A-modulated autophagy and apoptosis in Triple-negative Breast Cancer. Zhen Yongqi,Zhao Rongyan,Wang Minjuan,Jiang Xing,Gao Feng,Fu Leilei,Zhang Lan,Zhou Xian-Li Theranostics Triple-negative breast cancer (TNBC) is one of the most prevalent neoplastic diseases worldwide, but efficacious treatments for this pathological condition are still challenging. The lack of an effective targeted therapy also leads to a poor prognosis for patients affected by TNBC. In the present study, we repurposed the distinctive inhibitory effects of flubendazole, a traditional anthelmintic drug, towards the putative modulation of proliferation and migration of TNBC . According to a series of experimental approaches, including immunofluorescence (IF), immunoblotting (IB), siRNA and GFP-mRFP-LC3 plasmid transfection, respectively, we have found that flubendazole is capable of inducing autophagic cell death and apoptosis, thus exerting some anti-proliferative and anti-migration activity in TNBC cells. The therapeutic effects of flubendazole were evaluated by xenograft mouse models, followed by immunohistochemistry (IHC), IF and IB. Changes in the gene expression profiles of flubendazole-treated TNBC cells were analyzed by RNA sequencing (RNA-seq) and validated by IB. The potential binding mode of flubendazole and EVA1A was predicted by molecular docking and demonstrated by site-directed mutagenesis. We have presently found that flubendazole exhibits a considerable anti-proliferative activity and . Mechanistically, the induction of autophagic cell death appears to be pivotal for flubendazole-mediated growth inhibition of TNBC cells, whereas blocking autophagy was able to improve the survival rate and migration ability of flubendazole-treated TNBC cells. Specifically, RNA-seq analysis showed that flubendazole treatment could promote the up-regulation of EVA1A. Flubendazole may regulate autophagy and apoptosis by targeting EVA1A, thus affecting the mechanisms of TNBC proliferation and migration. Furthermore, Thr113 may be the key amino acid residues for the binding of flubendazole to EVA1A. Our results provide novel insights towards the putative anti-cancer efficacy of flubendazole. Furthermore, here we show that flubendazole could serve as a potential therapeutic drug in TNBC. Altogether, this study highlights the possibility of this repurposed autophagic inducer for future cancer treatments. 10.7150/thno.43473
Autophagy inhibition mediated by MCOLN1/TRPML1 suppresses cancer metastasis via regulating a ROS-driven TP53/p53 pathway. Autophagy Compelling evidence has demonstrated that macroautophagy/autophagy plays an important role in regulating multiple steps of metastatic cascades; however, the precise role of autophagy in metastasis remains unclear. This study demonstrates that autophagy inhibition induced by MCOLN1/TRPML1 suppresses cancer metastasis by evoking the ROS-mediated TP53/p53 pathway. First, we found that MCOLN1-mediated autophagy inhibition not only profoundly inhibits both migration and invasion in malignant melanoma and glioma cell lines , but also suppresses melanoma metastasis . Second, our study reveals that autophagy inhibition induced by MCOLN1 leads to damaged mitochondria accumulation followed by large quantities of ROS release. Third, we demonstrate that the elevated ROS resulting from autophagy inhibition subsequently triggers TP53 activity, which in turn modulates expression of its downstream targets that are involved in a broad spectrum of the metastatic cascade to suppress metastasis including MMP members and TWIST. In summary, our findings have established a mechanism by which autophagy inhibition suppresses metastasis via the ROS-TP53 signaling pathway. More importantly, our study demonstrates that autophagy inhibition through stimulation of MCOLN1 could evidently be one of the therapeutic potentials for combating cancer metastasis. 3-MA: 3-methyladenine; AA: amino acid; ATG5: autophagy related 5; ATG12: autophagy-related 12; Baf-A1: bafilomycin A; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CQ: chloroquine; DMEM: Dulbecco's Modified Eagle Medium; EMT: epithelial-mesenchymal transition; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HEK: human embryonic kidney; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MMP: matrix metallopeptidase; NC: negative control; NRK: normal rat kidney; PBS: phosphate-buffered saline; shRNA: short hairpin RNA; siRNA: short interfering RNA; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like autophagy-activating kinase 1. 10.1080/15548627.2021.2008752
Betulin Inhibits Lung Metastasis by Inducing Cell Cycle Arrest, Autophagy, and Apoptosis of Metastatic Colorectal Cancer Cells. Han Yo-Han,Mun Jeong-Geon,Jeon Hee Dong,Kee Ji-Ye,Hong Seung-Heon Nutrients BACKGROUND:Colorectal cancer (CRC) is one of the diseases with high prevalence and mortality worldwide. In particular, metastatic CRC shows low probability of surgery and lacks proper treatment. In this study, we conducted experiments to investigate the inhibitory effect of betulin against metastatic CRC and related mechanisms. METHODS:Water-soluble tetrazolium assay was used to determine the effect of betulin on metastatic CRC cell viability. Flow cytometry and TUNEL assay were performed to confirm whether betulin can induce apoptosis, autophagy, and cell cycle arrest. A lung metastasis mouse model was employed to estimate the anti-metastatic effect of betulin. RESULTS:betulin decreased viability of metastatic CRC cells, including CT26, HCT116, and SW620 cell lines. Through PI3K/Akt/mTOR inactivation, betulin induced AMPK-mediated G0/G1 phase arrest and autophagy of CT26 and HCT116 cells. In addition, betulin occurred caspase-dependent apoptosis via the mitogen-activated protein kinase signaling pathway in metastatic CRC cells. Moreover, orally administered betulin significantly inhibited metastasis of CT26 cells to the lung. CONCLUSION:Our results demonstrate the anti-metastatic effect and therapeutic potential of betulin in metastatic CRC treatment. 10.3390/nu12010066
Inhibition of PIKfyve using YM201636 suppresses the growth of liver cancer via the induction of autophagy. Hou Jiu-Zhou,Xi Zhuo-Qing,Niu Jie,Li Wei,Wang Xiao,Liang Chao,Sun Hua,Fang Dong,Xie Song-Qiang Oncology reports Liver cancer is among the most common types of cancer worldwide. The aim of the present study was to investigate whether the phosphatidylinositol‑3‑phosphate 5‑kinase (PIKfyve) inhibitor, YM201636, exerts anti‑proliferative effects on liver cancer. The methods used in the present study included MTT assay, flow cytometry, western blot analysis and an allograft mouse model of liver cancer. The results revealed that YM201636 inhibited the proliferation of HepG2 and Huh‑7 cells in a dose‑dependent manner. HepG2 and Huh‑7 cells exhibited strong monodansylcadaverine staining following treatment with YM201636. Accordingly, YM201636 treatment increased the expression of the autophagosome‑associated marker protein microtubule‑associated 1A/1B light chain 3‑II in HepG2 and Huh‑7 cells. The autophagy inhibitor 3‑methyladenine attenuated the inhibitory effects of YM201636 on liver cancer cell proliferation. Further in vivo analysis revealed that YM201636 (2 mg/kg) inhibited tumor growth without notable systemic toxicity. Mechanistic experiments demonstrated that YM201636 induced‑autophagy is dependent upon epidermal growth factor receptor (EGFR) overexpression in HepG2 and Huh‑7 cells. Collectively, these results suggested that the PIKfyve inhibitor YM201636 may inhibit tumor growth by promoting EGFR expression. This indicates that PIKfyve may be a potential therapeutic target for the treatment of liver cancer. 10.3892/or.2018.6928
Functions and Implications of Autophagy in Colon Cancer. Devenport Samantha N,Shah Yatrik M Cells Autophagy is an essential function to breakdown cellular proteins and organelles to recycle for new nutrient building blocks. In colorectal cancer, the importance of autophagy is becoming widely recognized as it demonstrates both pro- and anti-tumorigenic functions. In colon cancer, cell autonomous and non-autonomous roles for autophagy are essential in growth and progression. However, the mechanisms downstream of autophagy (to reduce or enhance tumor growth) are not well known. Additionally, the signals that activate and coordinate autophagy for tumor cell growth and survival are not clear. Here, we highlight the context- and cargo-dependent role of autophagy in proliferation, cell death, and cargo breakdown. 10.3390/cells8111349
IP Receptor Biology and Endoplasmic Reticulum Calcium Dynamics in Cancer. Parys Jan B,Bultynck Geert,Vervliet Tim Progress in molecular and subcellular biology Intracellular Ca signaling regulates a plethora of cellular functions. A central role in these processes is reserved for the inositol 1,4,5-trisphosphate receptor (IPR), a ubiquitously expressed Ca-release channel, mainly located in the endoplasmic reticulum (ER). Three IPR isoforms (IPR1, IPR2 and IPR3) exist, encoded respectively by ITPR1, ITPR2 and ITPR3. The proteins encoded by these genes are each about 2700 amino acids long and assemble into large tetrameric channels, which form the target of many regulatory proteins, including several tumor suppressors and oncogenes. Due to the important role of the IPRs in cell function, their dysregulation is linked to multiple pathologies. In this review, we highlight the complex role of the IPR in cancer, as it participates in most of the so-called "hallmarks of cancer". In particular, the IPR directly controls cell death and cell survival decisions via regulation of autophagy and apoptosis. Moreover, the IPR impacts cellular proliferation, migration and invasion. Typical examples of the role of the IPRs in these various processes are discussed. The relative levels of the IPR isoforms expressed and their subcellular localization, e.g. at the ER-mitochondrial interface, is hereby important. Finally, evidence is provided about how the knowledge of the regulation of the IPR by tumor suppressors and oncogenes can be exploited to develop novel therapeutic approaches to fight cancer. 10.1007/978-3-030-67696-4_11
Autophagy suppresses tumorigenesis through elimination of p62. Mathew Robin,Karp Cristina M,Beaudoin Brian,Vuong Nhan,Chen Guanghua,Chen Hsin-Yi,Bray Kevin,Reddy Anupama,Bhanot Gyan,Gelinas Celine,Dipaola Robert S,Karantza-Wadsworth Vassiliki,White Eileen Cell Allelic loss of the essential autophagy gene beclin1 occurs in human cancers and renders mice tumor-prone suggesting that autophagy is a tumor-suppression mechanism. While tumor cells utilize autophagy to survive metabolic stress, autophagy also mitigates the resulting cellular damage that may limit tumorigenesis. In response to stress, autophagy-defective tumor cells preferentially accumulated p62/SQSTM1 (p62), endoplasmic reticulum (ER) chaperones, damaged mitochondria, reactive oxygen species (ROS), and genome damage. Moreover, suppressing ROS or p62 accumulation prevented damage resulting from autophagy defects indicating that failure to regulate p62 caused oxidative stress. Importantly, sustained p62 expression resulting from autophagy defects was sufficient to alter NF-kappaB regulation and gene expression and to promote tumorigenesis. Thus, defective autophagy is a mechanism for p62 upregulation commonly observed in human tumors that contributes directly to tumorigenesis likely by perturbing the signal transduction adaptor function of p62-controlling pathways critical for oncogenesis. 10.1016/j.cell.2009.03.048