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Lithocholic acid induces endoplasmic reticulum stress, autophagy and mitochondrial dysfunction in human prostate cancer cells
- Source :
- PeerJ, vol 4, iss 11, PeerJ, PeerJ, Vol 4, p e2445 (2016), PeerJ, PeerJ, 2016, 4, pp.e2445. ⟨10.7717/peerj.2445⟩, Gafar, AA; Draz, HM; Goldberg, AA; Bashandy, MA; Bakry, S; Khalifa, MA; et al.(2016). Lithocholic acid induces endoplasmic reticulum stress, autophagy and mitochondrial dysfunction in human prostate cancer cells. PeerJ, 2016(11). doi: 10.7717/peerj.2445. UC Office of the President: Research Grants Program Office (RGPO). Retrieved from: http://www.escholarship.org/uc/item/0gk6b6zk
- Publication Year :
- 2016
- Publisher :
- eScholarship, University of California, 2016.
-
Abstract
- Lithocholic acid (LCA) is a secondary bile acid that is selectively toxic to human neuroblastoma, breast and prostate cancer cells, whilst sparing normal cells. We previously reported that LCA inhibited cell viability and proliferation and induced apoptosis and necrosis of androgen-dependent LNCaP and androgen-independent PC-3 human prostate cancer cells. In the present study, we investigated the roles of endoplasmic reticulum (ER) stress, autophagy and mitochondrial dysfunction in the toxicity of LCA in PC-3 and autophagy deficient, androgen-independent DU-145 cells. LCA induced ER stress-related proteins, such as CCAAT-enhancer-binding protein homologous protein (CHOP), and the phosphorylation of eukaryotic initiation factor 2-alpha (p-eIF2α) and c-Jun N-terminal kinases (p-JNK) in both cancer cell-types. The p53 upregulated modulator of apoptosis (PUMA) and B cell lymphoma-like protein 11 (BIM) levels were decreased at overtly toxic LCA concentrations, although PUMA levels increased at lower LCA concentrations in both cell lines. LCA induced autophagy-related conversion of microtubule-associated proteins 1A/1B light chain 3B (LC3BI–LC3BII), and autophagy-related protein ATG5 in PC-3 cells, but not in autophagy-deficient DU-145 cells. LCA (>10 µM) increased levels of reactive oxygen species (ROS) concentration-dependently in PC-3 cells, whereas ROS levels were not affected in DU-145 cells. Salubrinal, an inhibitor of eIF2αdephosphorylation and ER stress, reduced LCA-induced CHOP levels slightly in PC-3, but not DU-145 cells. Salubrinal pre-treatment increased the cytotoxicity of LCA in PC-3 and DU-145 cells and resulted in a statistically significant loss of cell viability at normally non-toxic concentrations of LCA. The late-stage autophagy inhibitor bafilomycin A1 exacerbated LCA toxicity at subtoxic LCA concentrations in PC-3 cells. The antioxidantα-tocotrienol strongly inhibited the toxicity of LCA in PC-3 cells, but not in DU-145 cells. Collectively, although LCA induces autophagy and ER stress in PC-3 cells, these processes appear to be initially of protective nature and subsequently consequential to, but not critical for the ROS-mediated mitochondrial dysfunction and cytotoxicity of LCA. The full mechanism of LCA-induced mitochondrial dysfunction and cytotoxicity in the similarly sensitive DU-145 cells remains to be elucidated.
- Subjects :
- 0301 basic medicine
Aging
genetic structures
[SDV]Life Sciences [q-bio]
lcsh:Medicine
Toxicology
Medical and Health Sciences
Salubrinal
chemistry.chemical_compound
0302 clinical medicine
RWPE-1
2.1 Biological and endogenous factors
Aetiology
Cancer
biology
General Neuroscience
Prostate Cancer
Lithocholic acid
General Medicine
Biological Sciences
3. Good health
Cell biology
Biochemistry
Oncology
030220 oncology & carcinogenesis
Endoplasmic reticulum stress
Prostate cancer cells
General Agricultural and Biological Sciences
Cell death
Urologic Diseases
Programmed cell death
ATG5
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
Rare Diseases
LNCaP
Autophagy
p53 upregulated modulator of apoptosis
Endoplasmic reticulum
Tocotrienol
lcsh:R
eye diseases
030104 developmental biology
Orphan Drug
chemistry
Pc-3
Cancer cell
biology.protein
Du-145
sense organs
Reactive oxygen species
Subjects
Details
- ISSN :
- 21678359
- Database :
- OpenAIRE
- Journal :
- PeerJ, vol 4, iss 11, PeerJ, PeerJ, Vol 4, p e2445 (2016), PeerJ, PeerJ, 2016, 4, pp.e2445. ⟨10.7717/peerj.2445⟩, Gafar, AA; Draz, HM; Goldberg, AA; Bashandy, MA; Bakry, S; Khalifa, MA; et al.(2016). Lithocholic acid induces endoplasmic reticulum stress, autophagy and mitochondrial dysfunction in human prostate cancer cells. PeerJ, 2016(11). doi: 10.7717/peerj.2445. UC Office of the President: Research Grants Program Office (RGPO). Retrieved from: http://www.escholarship.org/uc/item/0gk6b6zk
- Accession number :
- edsair.doi.dedup.....b28e6a8b0e754b7bec13e9af79ef15f4
- Full Text :
- https://doi.org/10.7717/peerj.2445⟩