Multiple mechanisms of Rottlerin toxicity in A375 melanoma cells.

Multiple mechanisms of Rottlerin toxicity in A375 melanoma cells.

Publication date: Aug 13, 2019

Rottlerin is a cytostatic and cytotoxic drug in a variety of cancer cells. Our previous experience demonstrated that depending upon the genetic/biochemical background of cancer cells, rottlerin is able to induce both apoptotic and autophagic cell death, or dramatically disturb protein homeostasis leading to lethal cellular atrophy. In the current study, we investigated the cytotoxic effects and mechanisms of rottlerin against human amelanotic A375 melanoma cells. In this cell line, rottlerin exhibits its main and newest cytotoxic properties, that is, growth arrest, apoptosis induction, and translation shutoff. In fact, the drug, time-, and dose-dependently, markedly inhibited cell proliferation through cyclin D1 downregulation and induced apoptotic cell death as early as after 18 h treatment. Mechanistically, rottlerin triggered apoptosis by both intrinsic and extrinsic pathways. Both pathways are likely activated by the downregulation of the antiapoptotic B-cell lymphoma 2 (Bcl-2) protein, which simultaneously affects mitochondrial and endoplasmic reticulum (ER) membranes stability. Concomitantly to extrinsic apoptosis induction, the rottlerin-activated ER stress/eukaryotic initiation factor 2 (eIF2) α axis blocked the translational apparatus. The altered proteostasis precluded the complete cells’ rescue from death in the presence of apoptosis inhibitors.

Ietta, F., Valacchi, G., Benincasa, L., Pecorelli, A., Cresti, L., and Maioli, E. Multiple mechanisms of Rottlerin toxicity in A375 melanoma cells. 23719. 2019 Biofactors.

Concepts Keywords
Apoptosis Branches of biology
Apoptotic Cell biology
Atrophy Programmed cell death
Autophagic Cellular senescence
B Cell Cell signaling
Biochemical Cellular processes
Cyclin Apoptosis
Cytostatic Bcl-2
Cytotoxic Cytostasis
Cytotoxic Drug Apoptosis
Downregulation
EIF2
Endoplasmic Reticulum
ER
Eukaryotic Initiation Factor
Genetic
Homeostasis
Lymphoma
Melanoma
Mitochondrial
Protein
Stress
Toxicity

Semantics

Type Source Name
disease MESH death
disease DOID B-cell lymphoma
disease MESH B-cell lymphoma
gene UNIPROT PCNA
pathway BSID Translation
pathway BSID Apoptosis
disease MESH growth
disease MESH atrophy
disease DOID cancer
disease MESH cancer
pathway BSID Melanoma
disease DOID melanoma
disease MESH melanoma

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