Search

Abstract Background Cell death induced by poly(ADP-ribose) (PAR) and mediated by apoptosis-inducing factor (AIF) is well-characterized in models of ischemic tissue injury, but their roles in cancer cell death after chemotherapy are less understood. Methods Here we investigated the roles of PAR and AIF by RNA interference (RNAi) in MDA-MB-231 and MCF-7 breast adenocarcinoma cells after chemotherapy. Differences in effects were statistically tested by analysis-of-variance and unpaired student’s t-test. Results Silencing of AIF by RNAi led to decreased MDA-MB-231 and MCF-7 breast cancer cell death after chemotherapy, which demonstrates a critical role for AIF. RNAi silencing of PAR glycohydrolase (PARG), the primary enzyme that catalyzes the hydrolysis of PAR, led to increased PAR levels but decreased cell death. Further investigation into the possible role of PAR in apoptosis revealed decreased caspase-3/7/8/9 activity in PARG-null cells. Interestingly, the pharmacologic inhibition of caspase activity in PARG-silenced breast cancer cells led to increased cell death after chemotherapy, which indicates that an alternative cell death pathway is activated due to elevated PAR levels and caspase inhibition. AIF silencing in these cells led to profound protection from chemotherapy, which demonstrates that the increased cell death after PARG silencing and caspase inhibition was mediated by AIF. Conclusions The results show a role for AIF in breast cancer cell death after chemotherapy, the ability of PAR to regulate caspase activity, and the ability of AIF to substitute as a primary mediator of breast cancer cell death in the absence of caspases. Thus, the induction of cell death by PAR/AIF may represent a novel strategy to optimize the eradication of breast tumors by activating an alternative cell death pathway.

Two analogues of the poly(ADP-ribose) glycohydrolase (PARG) inhibitor adenosine diphosphate (hydroxymethyl)pyrrolidinediol are synthesized and used in the photoaffinity labeling of PARG. These photoactive analogues are 2-azidoadenosine diphosphate (hydroxymethyl)pyrrolidinediol and 8-azidoadenosine diphosphate (hydroxymethyl)pyrrolidinediol (8-N3-ADP-HPD). Characterization of 8-N3-ADP-HPD has revealed that it can be utilized as a specific label for PARG.

The studies have shown that in poly(ADP-ribose) glycohydrolase (PARG) null embryonic trophoblast stem (TS) cells that the absence of PAR hydrolysis led to PAR-modified histones H1, H2A and H2B. It is shown that greater DNA accessibility, increased DNA damage, and increased cell death have contributed to the PARG null cell phenotype in response to genotoxic stress.

Results show that the inhibitor binding to poly(ADP-ribose)glycohydrolase is mediated by the tyrosine 796 residue by means of a ring stacking interaction as determined by a 8-fold decrease in catalytic activity when tyrosine is replaced with an alanine. Furthermore, a highly conserved region of the protein contains residues involved in catalytic activity and/or substrate recognition.

The article presents the political outlook for Southeast Asia for 2008-2009. In Brunei, the governmental system will remain to be highly centralized despite the fact that the district and village level councils have been provided some semblance of participatory parties. In Indonesia, it is predicted that there may be another Cabinet reshuffle in 2008 which relates to potential political splits between parties that supported the Yudhoyono-Kalla presidential ticket in 2004. In the Philippines, President Gloria Macapagal Arroyo is anticipated to encounter new street protests asking for her resignation and attempts to impeach her.

The article provides information on the political development of the Association of Southeast Asian Nations (ASEAN) members. It is inferred that Brunei Darussalam's prosperity was based on the buoyant oil prices which lead to the decision of Sultan Hassanal Bolkiah to increase the wages of civil servants. Philippines President Gloria Macapagal-Arroyo declared a week-long state of emergency in February 2006 because the military claimed to have foiled plans for a coup d'état being laid by some of their members. The victory of Prime Minister Lee Hsien Loong and the People's Action Party (PAP) during the general elections in Singapore on May 6, 2006 became the highlight in the country.