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Severe cellular stress activates apoptosis independently of p53 in osteosarcoma
- Source :
- Cell Death Discovery, Vol 7, Iss 1, Pp 1-9 (2021), Cell Death Discovery
- Publication Year :
- 2021
- Publisher :
- Nature Publishing Group, 2021.
-
Abstract
- Apoptosis induced by doxorubicin, bortezomib, or paclitaxel, targeting DNA, 26S proteasome, and microtubules respectively, was assessed in two osteosarcoma cells, p53 wild-type U2OS and p53-null MG63 cells. Doxorubicin-induced apoptosis only occurred in U2OS, not in MG63. In contrast, bortezomib and paclitaxel could drive U2OS or MG63 toward apoptosis effectively, suggesting that apoptosis induced by bortezomib or paclitaxel is p53-independent. The expressions of Bcl2 family members such as Bcl2, Bcl-xl, and Puma could be seen in U2OS and MG63 cells with or without doxorubicin, bortezomib, or paclitaxel treatment. In contrast, another member, Bim, only could be observed in U2OS, not in MG63, under the same conditions. Bim knockdown did not affect the doxorubicin-induced apoptosis in U2OS, suggested that a BH3-only protein other than Bim might participate in apoptosis induced by doxorubicin. Using a BH3-mimetic, ABT-263, to inhibit Bcl2 or Bcl-xl produced a limited apoptotic response in U2OS and MG63 cells, suggesting that this BH3-mimetic cannot activate the Bax/Bak pathway efficiently. Significantly, ABT-263 enhanced doxorubicin- and bortezomib-induced apoptosis synergistically in U2OS and MG63 cells. These results implied that the severe cellular stress caused by doxorubicin or bortezomib might be mediated through a dual process to control apoptosis. Respectively, doxorubicin or bortezomib activates a BH3-only protein in one way and corresponding unknown factors in another way to affect mitochondrial outer membrane permeability, resulting in apoptosis. The combination of doxorubicin with ABT-263 could produce synergistic apoptosis in MG63 cells, which lack p53, suggesting that p53 has no role in doxorubicin-induced apoptosis in osteosarcoma. In addition, ABT-263 enhanced paclitaxel to induce moderate levels of apoptosis.
- Subjects :
- Cancer Research
Immunology
Apoptosis
Article
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Puma
hemic and lymphatic diseases
medicine
Chemotherapy
Doxorubicin
neoplasms
RC254-282
Gene knockdown
biology
QH573-671
Bortezomib
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Cell Biology
biology.organism_classification
medicine.disease
Proteasome
Paclitaxel
chemistry
Cancer research
Osteosarcoma
biological phenomena, cell phenomena, and immunity
Cytology
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 20587716
- Volume :
- 7
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Cell Death Discovery
- Accession number :
- edsair.doi.dedup.....29c6067933e0af1a5514ccedaa7b22aa