Abstract
The DNA repair protein Cockayne syndrome group B (CSB) has been recently identified as a promising anticancer target. Suppression, by antisense technology, of this protein causes devastating effects on tumor cells viability, through a massive induction of apoptosis, while being non-toxic to non-transformed cells. To gain insights into the mechanisms underlying the pro-apoptotic effects observed after CSB ablation, global gene expression patterns were determined, to identify genes that were significantly differentially regulated as a function of CSB expression. Our findings revealed that response to endoplasmic reticulum stress and response to unfolded proteins were ranked top amongst the cellular processes affected by CSB suppression. The major components of the endoplasmic reticulum stress-mediated apoptosis pathway, including pro-apoptotic factors downstream of the ATF3-CHOP cascade, were dramatically up-regulated. Altogether our findings add new pieces to the understanding of CSB mechanisms of action and to the molecular basis of CS syndrome.
Highlights
Apoptosis evasion is a fundamental hallmark used by cancer cells to evolve resistance to cell death induced in response either to the intrinsic perturbation of metabolic circuitries or to anti-cancer drug therapies [1]
Microarray gene expression profile of Hela cells suppressed for Cockayne syndrome group B (CSB) protein We have recently shown that CSB ablation induces a pro-apoptotic effect [15]
Cells were incubated with antisense oligonucleotides inducing CSB mRNA degradation (ASO)
Summary
Apoptosis evasion is a fundamental hallmark used by cancer cells to evolve resistance to cell death induced in response either to the intrinsic perturbation of metabolic circuitries or to anti-cancer drug therapies [1]. The ability to evade apoptosis is caused by a range of different alterations including the over-expression of anti-apoptotic factors, which bring back to sublethal levels the stress conditions associated to cancer cell metabolism [2]. CSB participates in a number of different functions of a cell metabolism It plays a role in transcription-coupled repair (TCR), an important sub-pathway of nucleotide excision repair (NER) that rapidly removes bulky DNA lesions located on the transcribed strand of active genes [8]. CSB has been demonstrated to be a key regulator of p53, stimulating its ubiquitination and degradation, re-equilibrating the physiological response toward cell proliferation and survival rather than cell cycle arrest and cell death upon stress [11,12,13] Along these lines we speculated that CSB functions as an antiapoptotic factor [14]
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