Lysosomal involvement in cell death and cancer

Kirkegaard, Tove; Jäättelä, Marja

doi:10.1016/j.bbamcr.2008.09.008

Cited by 355 publications

(288 citation statements)

References 122 publications

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“…Importantly, transformation is associated with an increase in the volume and activity of the lysosomal compartment and even highly apoptosis-resistant cancer cells are frequently prone to cell death pathways mediated by lysosomal cathepsins (36,37). The data presented above add BAMLET to the growing list of cytotoxic agents that can induce a nonapoptotic lysosomal cell death pathway (35). In light of these data, combination therapies with agents further sensitizing cells to lysosomal destabilization (such as microtubule disturbing drugs vincristine and paclitaxel) as well as with those inducing lysosomal destabilization (such as siramesine) should be experimentally tested (38,39).…”

Section: Discussionmentioning

confidence: 99%

“…Among them are the lysosomes with their large arsenal of proteolytic and lipolytic hydrolases (4,34,35). Importantly, transformation is associated with an increase in the volume and activity of the lysosomal compartment and even highly apoptosis-resistant cancer cells are frequently prone to cell death pathways mediated by lysosomal cathepsins (36,37).…”

Section: Discussionmentioning

confidence: 99%

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BAMLET Activates a Lysosomal Cell Death Program in Cancer Cells

Rammer

Groth‐Pedersen

Kirkegaard

et al. 2010

Molecular Cancer Therapeutics

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A complex of human α-lactalbumin and oleic acid (HAMLET) was originally isolated from human milk as a potent anticancer agent. It kills a wide range of transformed cells of various origins while leaving nontransformed healthy cells largely unaffected both in vitro and in vivo. Importantly, purified α-lactalbumins from other mammals form complexes with oleic acid that show biological activities similar to that of HAMLET. The mechanism by which these protein-lipid complexes kill tumor cells is, however, largely unknown. Here, we show that complex of bovine α-lactalbumin and oleic acid (BAMLET), the bovine counterpart of HAMLET, kills tumor cells via a mechanism involving lysosomal membrane permeabilization. BAMLET shows potent cytotoxic activity against eight cancer cell lines tested, whereas nontransformed NIH-3T3 murine embryonic fibroblasts are relatively resistant. BAMLET accumulates rapidly and specifically in the endolysosomal compartment of tumor cells and induces an early leakage of lysosomal cathepsins into the cytosol followed by the activation of the proapoptotic protein Bax. Ectopic expression of three proteins known to stabilize the lysosomal compartment, i.e. heat shock protein 70 (Hsp70), Hsp70-2, and lens epithelium-derived growth factor, confer significant protection against BAMLET-induced cell death, whereas the antiapoptotic protein Bcl-2, caspase inhibition, and autophagy inhibition fail to do so. These data indicate that BAMLET triggers lysosomal cell death pathway in cancer cells, thereby clarifying the ability of α-lactalbumin:oleate complexes to kill highly apoptosis-resistant tumor cells. Mol Cancer Ther; 9(1); 24-32. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

BAMLET Activates a Lysosomal Cell Death Program in Cancer Cells

Rammer

Groth‐Pedersen

Kirkegaard

et al. 2010

Molecular Cancer Therapeutics

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120

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“…Besides being tagged for ubiquitin mediated degradation by c-Cbl, the ligand activated EGFR molecules are also degraded by lysosomal proteases, which is mediated via clathrin-coated pits involving endosomal pathway. Mutations and expression anomalies of genes regulating both proteasome and lysosomal degradation pathways have been reported in several carcinomas (Kirkegaard et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Tyrosine 1045 Codon Mutations in Exon 27 of EGFR are Infrequent in Oral Squamous Cell Carcinomas

Tushar

Ramanathan²

2013

Asian Pacific Journal of Cancer Prevention

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Background: The activation and inactivation of receptor tyrosine kinases are tightly regulated to ensure faithful replication of cells. After having transduced extracellular growth activating signals, activated EGFR is subjected to downregulation either by clathrin mediated endocytosis or c-Cbl mediated proteasome degradation depending on the ligand concentration. c-Cbl is an ubiquitin ligase which requires a phosphorylated tyrosine residue at position 1045 in the cytoplasmic domain of EGFR to interact and add ubiquitin molecules. While activating mutations in exons 19 and 21 have been associated with the development of several cancers, the status of mutations at tyrosine 1045 coding exon 27 of EGFR remain to be investigated. Consistently, defective phosphorylation at 1045 has been associated with sustained phosphorylation of EGFR in non-small lung carcinomas. Hence in the present study we investigated the genetic status of the tyrosine 1045 coding site within exon 27 of EGFR gene to explore for possible occurrence of mutations in this region, especially since no studies have addressed this issue so far. Materials and Methods: Tumor chromosomal DNA isolated from thirty five surgically excised oral squamous cell carcinoma tissues was subjected to PCR amplification with intronic primers flanking the tyrosine 1045 coding exon 27 of EGFR gene. The PCR amplicons were subsequently subjected to direct sequencing to elucidate the mutation status. Results: Sequence analysis identified no mutations in the tyrosine 1045 codon of EGFR in any of the thirty five samples that were analyzed. Conclusions: The lack of identification of mutation in the tyrosine 1045 codon of EGFR suggests that mutations in this region may be relatively rare in oral squamous cell carcinomas. To the best of our knowledge, this study is the first to have explored the genetic status of exon 27 of EGFR in oral squamous cell carcinoma tissue samples.

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“…The resistance induced by LAMP3 is primarily directed towards proteasome inhibitors used during chemotherapy. In conclusion, it has been found that increased expression of LAMP3 contributes to the development of autophagy and cell survival [6] [27]. It is important when developing new therapies, including molecularly targeted therapies, to inhibit the specific cytokine activating the signaling pathway involved in a particular disease.…”

Section: Discussionmentioning

confidence: 99%

The Transcriptional Activity of LAMP3 Gene Involved in Autophagocytosis in Colorectal Cancer LAMP3 Expression in Colorectal Cancer

Bednarczyk¹,

Muc-Wierzgoń²,

Zmarzły³

et al. 2017

JBM

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Background: Autophagocytosis is a biological process involving the controlled distribution of cell fragments and organelles in order to obtain an additional source of energy. LAMP3 (lysosome-associated membrane protein 3) is a heavily glycosylated integral membrane protein located mainly in the lysosomal membrane. Recent studies have shown that it participates in tumor metastasis and drug resistance. Its main role is contribution to tumor cells proliferation, migration and invasion. The aim of this study was to determine changes in transcriptional activity of LAMP3 at various stages of colorectal cancer. In addition, an attempt was made to select miRNAs potentially regulating LAMP3 expression using bioinformatic databases. Methods: The study was conducted on healthy colon samples and colon cancer samples in four stages. Molecular analysis included the extraction of total RNA, purification of the obtained extracts, expression profile analysis using oligonucleotide microarray technique and in silico determination of miRNAs potentially regulating the LAMP3 expression. Results: The level of LAMP3 expression is higher in colorectal adenocarcinoma cells than in non-cancerous cells and depends on the stage of the disease. Conclusions: LAMP3 may promote cancer progression, metastasis and cause the resistance to treatment.

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Lysosomal involvement in cell death and cancer

Cited by 355 publications

References 122 publications

BAMLET Activates a Lysosomal Cell Death Program in Cancer Cells

BAMLET Activates a Lysosomal Cell Death Program in Cancer Cells

Tyrosine 1045 Codon Mutations in Exon 27 of EGFR are Infrequent in Oral Squamous Cell Carcinomas

The Transcriptional Activity of LAMP3 Gene Involved in Autophagocytosis in Colorectal Cancer LAMP3 Expression in Colorectal Cancer

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