Lysosomal Biology in Cancer

Fennelly, Colin; Amaravadi, Ravi K.

doi:10.1007/978-1-4939-6934-0_19

Cited by 84 publications

(70 citation statements)

References 128 publications

(120 reference statements)

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“…Movement of lysosomes towards the cell periphery is also observed in cancer cell lines and is required for cancer invasion, migration, and metastasis [24,44]. In this case, lysosomal exocytosis occurs, leading to the secretion of acidic hydrolases and metalloproteinases that are required for degradation of the extracellular matrix to promote metastasis of cancer cells [45,46]. Recently, inhibition of AC was found to cause suppression of the interaction between lysosomes and the multivesicular body, and hence the increase of exosome release from podocytes, highlighting the role of AC in TRPML1 channel-mediated Ca 2+ release [47].…”

Section: Discussionmentioning

confidence: 99%

Acid Ceramidase Depletion Impairs Neuronal Survival and Induces Morphological Defects in Neurites Associated with Altered Gene Transcription and Sphingolipid Content

Kyriakou

Lederer

Kleanthous

et al. 2020

IJMS

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The ASAH1 gene encodes acid ceramidase (AC), an enzyme that is implicated in the metabolism of ceramide (Cer). Mutations in the ASAH1 gene cause two different disorders, Farber disease (FD), a rare lysosomal storage disorder, and a rare form of spinal muscular atrophy combined with progressive myoclonic epilepsy (SMA-PME). In the absence of human in vitro neuronal disease models and to gain mechanistic insights into pathological effects of ASAH1 deficiency, we established and characterized a stable ASAH1 knockdown (ASAH1KD) SH-SY5Y cell line. ASAH1KD cells displayed reduced proliferation due to elevated apoptosis and G1/S cell cycle arrest. Distribution of LAMP1-positive lysosomes towards the cell periphery and significantly shortened and less branched neurites upon differentiation, implicate AC for lysosome positioning and neuronal development, respectively. Lipidomic analysis revealed changes in the intracellular levels of distinct sphingolipid species, importantly without Cer accumulation, in line with altered gene transcription within the sphingolipid pathway. Additionally, the transcript levels for Rho GTPases (RhoA, Rac1, and Cdc42), which are key regulators of axonal orientation, neurite branching and lysosome positioning were found to be dysregulated. This study shows the critical role of AC in neurons and suggests how AC depletion leads to defects seen in neuropathology of SMA-PME and FD.

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Section: Discussionmentioning

confidence: 99%

Acid Ceramidase Depletion Impairs Neuronal Survival and Induces Morphological Defects in Neurites Associated with Altered Gene Transcription and Sphingolipid Content

Kyriakou

Lederer

Kleanthous

et al. 2020

IJMS

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“…Lysosomes recycle organelles and proteins in cells [50] and they play extensive roles in various diseases, including cancers, making them an attractive and targetable node for therapeutic intervention. In liver cancer, lysosomes are known to be involved in the chemoresistance of HCC cells [51,52]. Here, we used LysoTracker probes to assess the lysosomal contents of cells and found that FAM215A had a positive effect on the lysosomal content of HCC cells.…”

Section: Discussionmentioning

confidence: 91%

Dysregulated FAM215A Stimulates LAMP2 Expression to Confer Drug-Resistant and Malignant in Human Liver Cancer

Huang

Lin

Cheng

et al. 2020

Cells

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Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies worldwide. Long non-coding (lnc) RNAs regulate complex cellular functions, such as cell growth, differentiation, metabolism, and metastasis. Although deregulation of lncRNA expression has been detected in HCC, many of the hepato-carcinogenesis-associated lncRNAs remain yet unidentified. Here, we aimed to investigate the involvement of a specific HCC-dysregulated lncRNA, FAM215A, and characterize its molecular regulation mechanism. We show for the first time that FAM215A is overexpressed in HCC, and its expression level correlates with tumor size, vascular invasion, and pathology stage. Overexpression of FAM215A accelerates cell proliferation and metastasis in HCC cells. According to Gene Expression Omnibus Dataset analysis, FAM215A is induced in doxorubicin (DOX)-resistant HCC cells. Overexpression of FAM215A increases DOX resistance in two HCC cell lines, and this is associated with enhanced expression of lysosome-associated membrane protein 2 (LAMP2). FAM215A interacts with LAMP2 to protect it from ubiquitination. Together, our results show that the lncRNA, FAM215A, is highly expressed in HCC, where it interacts with and stabilizes LAMP2 to increase tumor progression while decreasing doxorubicin sensitivity.

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“…An acidic environment is necessary for autophagosome–lysosome fusion in mammalian cells. An increasing pH has the same inhibitory effect on the fusion process as the anti‐autophagic macrolide bafilomycin A1, although the latter cannot inhibit the fusion process resulting in amphisome formation (Kawai et al , ; Klionsky et al , ; Fennelly & Amaravadi, ).…”

Section: Convergence Of Autophagy and Endocytosismentioning

confidence: 99%

Molecular interplay of autophagy and endocytosis in human health and diseases

et al. 2019

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Autophagy, an evolutionarily conserved process for maintaining the physio-metabolic equilibrium of cells, shares many common effector proteins with endocytosis. For example, tethering proteins involved in fusion like Ras-like GTPases (Rabs), soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs), lysosomal-associated membrane protein (LAMP), and endosomal sorting complex required for transport (ESCRT) have a dual role in endocytosis and autophagy, and the trafficking routes of these processes converge at lysosomes. These common effectors indicate an association between budding and fusion of membrane-bound vesicles that may have a substantial role in autophagic lysosome reformation, by sensing cellular stress levels. Therefore, autophagy-endocytosis crosstalk may be significant and implicates a novel endocytic regulatory pathway of autophagy. Moreover, endocytosis has a pivotal role in the intake of signalling molecules, which in turn activates cascades that can result in pathophysiological conditions. This review discusses the basic mechanisms of this crosstalk and its implications in order to identify potential novel therapeutic targets for various human diseases.

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Lysosomal Biology in Cancer

Cited by 84 publications

References 128 publications

Acid Ceramidase Depletion Impairs Neuronal Survival and Induces Morphological Defects in Neurites Associated with Altered Gene Transcription and Sphingolipid Content

Acid Ceramidase Depletion Impairs Neuronal Survival and Induces Morphological Defects in Neurites Associated with Altered Gene Transcription and Sphingolipid Content

Dysregulated FAM215A Stimulates LAMP2 Expression to Confer Drug-Resistant and Malignant in Human Liver Cancer

Molecular interplay of autophagy and endocytosis in human health and diseases

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