Bid exhibits S phase checkpoint activation and plays a pro-apoptotic role in response to etoposide-induced DNA damage in hepatocellular carcinoma cells.
Bid has multiple functions in apoptosis, survival, and proliferation. The role of Bid in etoposide-induced-DNA damage in HCC has not been investigated. Here, we report that p53-overexpression led to the notable up-regulation of the expression of Bid protein, whereas the acquired expression of Bid by PLC/PRF/5 cells dramatically decreased the p53 level. Upon the administration of a high dose of etoposide (causing irreparable damage), Bid sensitized cells to apoptosis. However, at a low dose of etoposide (repairable damage), Bid activated the S phase checkpoint through the up-regulation of p21 and p27, which are both p53-independent. While the unrepairable damage was being carried out, Bid was quickly translocated to the mitochondria to release cytochrome c into the cytosol, which activated caspases 9 and 3 and led to cell death. In conclusion, our study demonstrates that Bid both exhibits S phase checkpoint activation and plays a pro-apoptotic role in response to different degrees of etoposide-induced DNA damage in HCC cells. The elucidation of these intricate mechanisms of Bid points to the development of a possible therapeutic option that combines cytotoxic therapies to treat HCC.
Song
Gang
G
Department of Surgery, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
Chen
George G
GG
Chau
Davor Kin-Fan
DK
Miao
Ji
J
Lai
Paul B S
PB
D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000502:physiology*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000502:physiology*; D015536:Down-Regulation; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms; D016196:S Phase / Q000187:drug effects / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D016159:Tumor Suppressor Protein p53; D005047:Etoposide