bims-lymeca 2022-01-09 papers

bims-lymeca

Biomed News

on Lysosome metabolism in cancer

Issue of 2022‒01‒09
thirteen papers selected by
Charilaos Filippakis
Harvard University

Multiple Mechanisms Converging on Transcription Factor EB Activation by the Natural Phenol Pterostilbene.
Deglycosylated EpCAM regulates proliferation by enhancing autophagy of breast cancer cells via PI3K/Akt/mTOR pathway.
A Compendium of Information on the Lysosome.
Target c-Myc to treat pancreatic cancer.
Adapted suspension tumor cells rewire metabolic pathways for anchorage-independent survival through AKT activation.
How to exploit different endocytosis pathways to allow selective delivery of anticancer drugs to cancer cells over healthy cells.
Isoform-dependent lysosomal degradation and internalization of Apolipoprotein E requires autophagy proteins.
Compression enhances invasive phenotype and matrix degradation of breast Cancer cells via Piezo1 activation.
DHOK Exerts Anti-Cancer Effect Through Autophagy Inhibition in Colorectal Cancer.
Dynamic supramolecular self-assembly of platinum(ii) complexes perturbs an autophagy-lysosomal system and triggers cancer cell death.
A novel halogenated adenosine analog 5'-BrDA displays potent toxicity against colon cancer cells in vivo and in vitro.
Tumor metastasis: Mechanistic insights and therapeutic interventions.
The Regulatory Mechanism Between Lysosomes and Mitochondria in the Etiology of Cardiovascular Diseases.

Oxid Med Cell Longev. 2021 ;2021 7658501

Multiple Mechanisms Converging on Transcription Factor EB Activation by the Natural Phenol Pterostilbene.

Martina La Spina, Michele Azzolini, Andrea Salmaso, Sofia Parrasia, Eva Galletta, Marco Schiavone, Martina Chrisam, Andrea Mattarei, Giulietta Di Benedetto, Andrea Ballabio, Natascia Tiso, Mario Zoratti, Lucia Biasutto.

Pterostilbene (Pt) is a potentially beneficial plant phenol. In contrast to many other natural compounds (including the more celebrated resveratrol), Pt concentrations producing significant effects in vitro can also be reached with relative ease in vivo. Here we focus on some of the mechanisms underlying its activity, those involved in the activation of transcription factor EB (TFEB). A set of processes leading to this outcome starts with the generation of ROS, attributed to the interaction of Pt with complex I of the mitochondrial respiratory chain, and spreads to involve Ca2+ mobilization from the ER/mitochondria pool, activation of CREB and AMPK, and inhibition of mTORC1. TFEB migration to the nucleus results in the upregulation of autophagy and lysosomal and mitochondrial biogenesis. Cells exposed to several μM levels of Pt experience a mitochondrial crisis, an indication for using low doses in therapeutic or nutraceutical applications. Pt afforded significant functional improvements in a zebrafish embryo model of ColVI-related myopathy, a pathology which also involves defective autophagy. Furthermore, long-term supplementation with Pt reduced body weight gain and increased transcription levels of Ppargc1a and Tfeb in a mouse model of diet-induced obesity. These in vivo findings strengthen the in vitro observations and highlight the therapeutic potential of this natural compound.

DOI: https://doi.org/10.1155/2021/7658501
Aging (Albany NY). 2022 Jan 04. 13(undefined):

Deglycosylated EpCAM regulates proliferation by enhancing autophagy of breast cancer cells via PI3K/Akt/mTOR pathway.

Liu Yang, Qijun Wang, Qian Zhao, Fan Yang, Tingjiao Liu, Xiaohua Huang, Qiu Yan, Xuesong Yang.

  Autophagy is an important regulator of cellular homeostasis and its dysregulation often results in cancer. Aberrant glycosylation induced by oncogenic transformation contributes to tumor invasion and metastasis. In a previous study, we have demonstrated that EpCAM, a glycosylation protein, is associated with cell growth and metastasis in breast cancer. But the effect of EpCAM glycosylation on autophagy is not clear. the precise mechanism of regulation remains largely unknown. In this study, breast cancer cells were transfected with N-glycosylation mutation EpCAM plasmid to express deglycosylated EpCAM. The result showed that deglycosylated EpCAM promoted autophagy in breast cancer cells. We further confirmed this conclusion with the activator (Rapamycin, RAP) and inhibitor (Wortmannin) of autophagy. We also found that deglycosylated EpCAM promoted apoptosis and inhibited proliferation through activating autophagy by suppressing Akt/mTOR signaling pathway in breast cancer cells. These findings represent a novel mechanism by which deglycosylated EpCAM inhibits proliferation by enhancing autophagy of breast cancer cells via PI3K/Akt/mTOR pathway. In conclusion, the combination of autophagy modulation and EpCAM targeted therapy is a promising therapeutic strategy in the treatment of breast cancer.

Keywords:  EpCAM; PI3K/Akt/mTOR; autophagy; breast cancer; glycosylation

DOI:  https://doi.org/10.18632/aging.203795
Front Cell Dev Biol. 2021 ;9 798262

A Compendium of Information on the Lysosome.

Nadia Bouhamdani, Dominique Comeau, Sandra Turcotte.

  For a long time, lysosomes were considered as mere waste bags for cellular constituents. Thankfully, studies carried out in the past 15 years were brimming with elegant and crucial breakthroughs in lysosome research, uncovering their complex roles as nutrient sensors and characterizing them as crucial multifaceted signaling organelles. This review presents the scientific knowledge on lysosome physiology and functions, starting with their discovery and reviewing up to date ground-breaking discoveries highlighting their heterogeneous functions as well as pending questions that remain to be answered. We also review the roles of lysosomes in anti-cancer drug resistance and how they undergo a series of molecular and functional changes during malignant transformation which lead to tumor aggression, angiogenesis, and metastases. Finally, we discuss the strategy of targeting lysosomes in cancer which could lead to the development of new and effective targeted therapies.

Keywords:  BORC; TFEB; autophagy; cancer; endocytosis; lysosome; mTOR; reformation

DOI:  https://doi.org/10.3389/fcell.2021.798262
Cancer Biol Ther. 2022 Jan 03. 1-17

Target c-Myc to treat pancreatic cancer.

Moein Ala.

  C-Myc overexpression is a common finding in pancreatic cancer and predicts the aggressive behavior of cancer cells. It binds to the promoter of different genes, thereby regulating their transcription. C-Myc is downstream of KRAS and interacts with several oncogenic and proliferative pathways in pancreatic cancer. C-Myc enhances aerobic glycolysis in cancer cells and regulates glutamate biosynthesis from glutamine. It provides enough energy for cancer cells' metabolism and sufficient substrate for the synthesis of organic molecules. C-Myc overexpression is associated with chemoresistance, intra-tumor angiogenesis, epithelial-mesenchymal transition (EMT), and metastasis in pancreatic cancer. Despite its title, c-Myc is not "undruggable" and recent studies unveiled that it can be targeted, directly or indirectly. Small molecules that accelerate c-Myc ubiquitination and degradation have been effective in preclinical studies. Small molecules that hinder c-Myc-MAX heterodimerization or c-Myc/MAX/DNA complex formation can functionally inhibit c-Myc. In addition, c-Myc can be targeted through transcriptional, post-transcriptional, and translational modifications.

Keywords:  BET inhibitor; C-myc; KRAS; chemoresistance; pancreatic cancer

DOI:  https://doi.org/10.1080/15384047.2021.2017223
Exp Cell Res. 2021 Dec 31. pii: S0014-4827(21)00561-9. [Epub ahead of print] 113005

Adapted suspension tumor cells rewire metabolic pathways for anchorage-independent survival through AKT activation.

Hyun Jeong Joo, Ga Eun Chung, Sora Han, Hye In Ka, Su Jung Soh, Young Yang.

  Metastatic spread of cancer cells is the main cause of cancer-related death. As cancer cells adapt themselves in a suspended state in the blood stream before penetration and regrowth at distal tissues, understanding their survival strategy in an anchorage-independent condition is important to develop appropriate therapeutics. We have previously generated adapted suspension cells (ASCs) from parental adherent cancer cells to study the characteristics of circulating tumor cells. In this study, we explored metabolic rewiring in MDA-MB-468 ASCs to adapt to suspension growth conditions through extracellular flux analyses and various metabolic assays. We also determined the relationship between AKT activation and metabolic rewiring in ASCs using the AKT inhibitor, MK2206. ASCs reprogramed metabolism to enhance glycolysis and basal oxygen consumption rate. RNA-sequencing analysis revealed the upregulation in the genes related to glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. The changes in the metabolic program led to a remarkable dependency of ASCs on carbohydrates as an energy source for proliferation as compared to parental adherent cells (ADs). AKT activation was observed in ASCs and those generated from pancreatic and other breast cancer cells, and AKT activation inhibition in ASCs decreased glycolysis and oxygen consumption. AKT activation is an important strategy for obtaining energy through the enhancement of glycolysis in ASCs. The regulation of AKT activity and/or glycolysis may provide a strong therapeutic strategy to prevent the metastatic spread of cancer cells.

Keywords:  AKT; Adapted suspension cell; Anchorage-independent growth; Circulating tumor cell; Glycolysis; Metabolism

DOI:  https://doi.org/10.1016/j.yexcr.2021.113005
Chem Sci. 2021 Dec 01. 12(46): 15407-15417

How to exploit different endocytosis pathways to allow selective delivery of anticancer drugs to cancer cells over healthy cells.

Vu Thanh Cong, Richard D Tilley, George Sharbeen, Phoebe A Phillips, Katharina Gaus, J Justin Gooding.

It was recently shown that it is possible to exploit the nanoparticle shape to selectively target endocytosis pathways found in cancer and not healthy cells. It is important to understand and compare the endocytosis pathways of nanoparticles in both cancer and healthy cells to restrict the healthy cells from taking up anticancer drugs to help reduce the side effects for patients. Here, the clathrin-mediated endocytosis inhibitor, hydroxychloroquine, and the anticancer drug, doxorubicin, are loaded into the same mesoporous silica nanorods. The use of nanorods was found to restrict the uptake by healthy cells but allowed cancer cells to take up the nanorods via the macropinocytosis pathway. Furthermore, it is shown that the nanorods can selectively deliver doxorubicin to the nucleus of breast cancer cells and to the cytoplasm of pancreatic cancer cells. The dual-drug-loaded nanorods were able to selectively kill the breast cancer cells in the presence of healthy breast cells. This study opens exciting possibilities of targeting cancer cells based on the material shape rather than targeting antibodies.

DOI: https://doi.org/10.1039/d1sc04656j
J Cell Sci. 2022 Jan 04. pii: jcs.258687. [Epub ahead of print]

Isoform-dependent lysosomal degradation and internalization of Apolipoprotein E requires autophagy proteins.

Gianna M Fote, Nicolette R Geller, Nikolaos Efstathiou, Nathan Hendricks, Demetrios G Vavvas, Jack C Reidling, Leslie M Thompson, Joan S Steffan.

  The human Apolipoprotein E4 isoform (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), and lysosomal dysfunction has been implicated in AD pathogenesis. We found in cells stably expressing each APOE isoform that APOE4 increases lysosomal trafficking, accumulates in enlarged lysosomes and late endosomes, alters autophagic flux and the abundance of autophagy proteins and lipid droplets, and alters the proteomic contents of lysosomes following internalization. We investigated APOE-related lysosomal trafficking further in cell culture, and found that APOE from the post-golgi compartment is degraded by autophagy. We found that this autophagic process requires the lysosomal membrane protein LAMP2 in immortalized neuron-like and hepatic cells and in mouse brain tissue. Several macroautophagy-associated proteins were also required for autophagic degradation and internalization of APOE in hepatic cells. The dysregulated autophagic flux and lysosomal trafficking of APOE4 that we observed suggest a possible novel mechanism that may contribute to AD pathogenesis.

Keywords:  APOE; APOE4; Alzheimer's disease; Chaperone-mediated autophagy; LC3-associated endocytosis

DOI:  https://doi.org/10.1242/jcs.258687
BMC Mol Cell Biol. 2022 Jan 03. 23(1): 1

Compression enhances invasive phenotype and matrix degradation of breast Cancer cells via Piezo1 activation.

Mingzhi Luo, Grace Cai, Kenneth K Y Ho, Kang Wen, Zhaowen Tong, Linhong Deng, Allen P Liu.

  BACKGROUND: Uncontrolled growth in solid breast cancer generates mechanical compression that may drive the cancer cells into a more invasive phenotype, but little is known about how such compression affects the key events and corresponding regulatory mechanisms associated with invasion of breast cancer cells including cellular behaviors and matrix degradation.RESULTS: Here we show that compression enhanced invasion and matrix degradation of breast cancer cells. We also identified Piezo1 as the putative mechanosensitive cellular component that transmitted compression to not only enhance the invasive phenotype, but also induce calcium influx and downstream Src signaling. Furthermore, we demonstrated that Piezo1 was mainly localized in caveolae, and both Piezo1 expression and compression-enhanced invasive phenotype of the breast cancer cells were reduced when caveolar integrity was compromised by either knocking down caveolin1 expression or depleting cholesterol content.
CONCLUSIONS: Taken together, our data indicate that mechanical compression activates Piezo1 channels to mediate enhanced breast cancer cell invasion, which involves both cellular events and matrix degradation. This may be a critical mechanotransduction pathway during breast cancer metastasis, and thus potentially a novel therapeutic target for the disease.

Keywords:  Breast cancer cell; Compression; Invasion; Piezo1

DOI:  https://doi.org/10.1186/s12860-021-00401-6
Front Cell Dev Biol. 2021 ;9 760022

DHOK Exerts Anti-Cancer Effect Through Autophagy Inhibition in Colorectal Cancer.

Yuhan Shu, Xin Sun, Guiqin Ye, Mengting Xu, Zhipan Wu, Caixia Wu, Shouxin Li, Jingkui Tian, Haote Han, Jianbin Zhang.

  DHOK (14,15β-dihydroxyklaineanone) is a novel diterpene isolated from roots of Eurycoma longifolia Jack, a traditional herb widely applied in Southeast Asia. It is reported that DHOK has cytotoxic effect on cancer cells, but its anti-cancer mechanism has still been not clear. In our study, we first observed that DHOK inhibits cell proliferation of colorectal cancer cells in a time- and dose-dependent manner. Next, we performed transcriptome sequencing to identify the targets of DHOK and found that autophagy-related signaling pathways are involved under DHOK treatment. Indeed, in DHOK-treated cells, the level of autophagosome marker LC3 and the formation of GFP-LC3 puncta were decreased, indicating the reduction of autophagy. Moreover, confocal microscopy results revealed the lysosomal activity and the formation of autolysosomes are also inhibited. Our western blotting results demonstrated the activation of mammalian target of rapamycin (mTOR) signaling pathway by DHOK, which may be attributed to the enhancement of ERK and AKT activity. Functionally, activation of autophagy attenuated DHOK-caused cell death, indicating that autophagy serves as cell survival. In xenograft mouse model, our results also showed that DHOK activates the mTOR signaling pathway, decreases autophagy level and inhibits the tumorigenesis of colon cancer. Taken together, we revealed the molecular mechanism of DHOK against cancer and our results also demonstrate great potential of DHOK in the treatment of colorectal cancer.

Keywords:  DHOK; autophagy; colorectal cancer; mTOR pathway; transcriptome sequencing

DOI:  https://doi.org/10.3389/fcell.2021.760022
Chem Sci. 2021 Dec 01. 12(46): 15229-15238

Dynamic supramolecular self-assembly of platinum(ii) complexes perturbs an autophagy-lysosomal system and triggers cancer cell death.

Ka-Chung Tong, Pui-Ki Wan, Chun-Nam Lok, Chi-Ming Che.

Self-assembly of platinum(ii) complexes to form supramolecular structures/nanostructures due to intermolecular ligand π-π stacking and metal-ligand dispersive interactions is widely used to develop functional molecular materials, but the application of such non-covalent molecular interactions has scarcely been explored in medical science. Herein is described the unprecedented biological properties of platinum(ii) complexes relevant to induction of cancer cell death via manifesting such intermolecular interactions. With conjugation of a glucose moiety to the planar platinum(ii) terpyridyl scaffold, the water-soluble complex [Pt(tpy)(C[triple bond, length as m-dash]CArOGlu)](CF3SO3) (1a, tpy = 2,2':6',2''-terpyridine, Glu = glucose) is able to self-assemble into about 100 nm nanoparticles in physiological medium, be taken up by lung cancer cells via energy-dependent endocytosis, and eventually transform into other superstructures distributed in endosomal/lysosomal and mitochondrial compartments apparently following cleavage of the glycosidic linkage. Accompanying the formation of platinum-containing superstructures are increased autophagic vacuole formation, lysosomal membrane permeabilization, and mitochondrial membrane depolarization, as well as anti-tumor activity of 1a in a mouse xenograft model. These findings highlight the dynamic, multi-stage extracellular and intracellular supramolecular self-assembly of planar platinum(ii) complexes driven by modular intermolecular interactions with potential anti-cancer application.

DOI: https://doi.org/10.1039/d1sc02841c
Toxicol Appl Pharmacol. 2021 Dec 31. pii: S0041-008X(21)00461-0. [Epub ahead of print] 115857

A novel halogenated adenosine analog 5'-BrDA displays potent toxicity against colon cancer cells in vivo and in vitro.

Long Ma, Yingying Lu, Yaqin Li, Zhizhen Yang, Yu Mao, Yi Wang, Shuli Man.

  Adenosine, as a naturally occurring nucleoside, plays an important role in human health maintenance. In recent years, many studies have shown that adenosine has the effect of cancer inhibition, and some of its analogs have been successfully marketed as anticancer drugs. This report mainly describes the anti-colon cancer activities and mechanism of a novel halogenated adenosine analog named 5'-bromodeoxyadenosine (5'-BrDA). As a result, 5'-BrDA concentration-dependently inhibited colon cancer cells proliferation, induced autophagy without disruption of lysosomal stability, and promoted autophagy-independently cellular mitochondrial apoptosis by increasing the accumulation of reactive oxygen species. Furthermore, 5'-BrDA inhibited the tumor growth of colon cancer in CT26 inbred mice without affecting the body weight in vivo. Collectively, the above-mentioned mechanisms contributed to the anticancer activity of 5'-BrDA. It is rare to discover novel anticancer adenosine analogs during the past couple of decades. We believe that our work will enrich the understanding of adenosine analogs, also, pave the way for adenosine analogs product based anticancer drug development.

Keywords:  Anti-colon cancer; Apoptosis; Autophagy; Halogenated adenosine analogue; ROS overproduction

DOI:  https://doi.org/10.1016/j.taap.2021.115857
MedComm (2020). 2021 Dec;2(4): 587-617

Tumor metastasis: Mechanistic insights and therapeutic interventions.

Mengmeng Liu, Jing Yang, Bushu Xu, Xing Zhang.

  Cancer metastasis is responsible for the vast majority of cancer-related deaths worldwide. In contrast to numerous discoveries that reveal the detailed mechanisms leading to the formation of the primary tumor, the biological underpinnings of the metastatic disease remain poorly understood. Cancer metastasis is a complex process in which cancer cells escape from the primary tumor, settle, and grow at other parts of the body. Epithelial-mesenchymal transition and anoikis resistance of tumor cells are the main forces to promote metastasis, and multiple components in the tumor microenvironment and their complicated crosstalk with cancer cells are closely involved in distant metastasis. In addition to the three cornerstones of tumor treatment, surgery, chemotherapy, and radiotherapy, novel treatment approaches including targeted therapy and immunotherapy have been established in patients with metastatic cancer. Although the cancer survival rate has been greatly improved over the years, it is still far from satisfactory. In this review, we provided an overview of the metastasis process, summarized the cellular and molecular mechanisms involved in the dissemination and distant metastasis of cancer cells, and reviewed the important advances in interventions for cancer metastasis.

Keywords:  cancer; epithelial‐mesenchymal transition; immunotherapy; metastasis; targeted therapy; tumor microenvironment

DOI:  https://doi.org/10.1002/mco2.100
Acta Physiol (Oxf). 2022 Jan 03. e13757

The Regulatory Mechanism Between Lysosomes and Mitochondria in the Etiology of Cardiovascular Diseases.

Mengxue Zhao, Andrew Lian, Li Zhong, Rui Guo.

  Coordinated action among various organelles maintain cellular functions. For instance, mitochondria and lysosomes are the main organelles contributing to cellular metabolism and provide energy for cardiomyocyte contraction. They also provide essential signaling platforms in the cell that regulate many key processes such as autophagy, apoptosis, oxidative stress, inflammation, and cell death. Often, abnormalities in mitochondrial or lysosomal structures and functions bring about cardiovascular disease (CVD). Although the communication between mitochondria and lysosomes throughout the cardiovascular system is intensely studied, the regulatory mechanisms have not been completely understood. We summarize the most recent studies related to mitochondria and lysosomes' role in CVDs and their potential connections and communications under cardiac pathophysiological conditions. Further we discuss limitations and future perspectives regarding diagnosis, therapeutic strategies, and drug discovery in CVDs.

Keywords:  autophagy; cardiovascular disease; interaction; lysosome; mechanism; metabolism; mitochondrion

DOI:  https://doi.org/10.1111/apha.13757