Abstract
Chemotherapy and radiation, the two most common cancer therapies, exert their anticancer effects by causing damage to cellular DNA. However, systemic treatment damages DNA not only in cancer, but also in healthy cells, resulting in the progression of serious side effects and limiting efficacy of the treatment. Interestingly, in response to DNA damage, p53 seems to play an opposite role in normal and in the majority of cancer cells—wild-type p53 mediates apoptosis in healthy tissues, attributing to the side effects, whereas mutant p53 often is responsible for acquired cancer resistance to the treatment. Here, we show that leucine zipper-containing ARF-binding protein (LZAP) binds and stabilizes p53. LZAP depletion eliminates p53 protein independently of its mutation status, subsequently protecting wild-type p53 cells from DNA damage-induced cell death, while rendering cells expressing mutant p53 more sensitive to the treatment. In human non-small-cell lung cancer, LZAP levels correlated with p53 levels, suggesting that loss of LZAP may represent a novel mechanism of p53 inactivation in human cancer. Our studies establish LZAP as a p53 regulator and p53-dependent determinative of cell fate in response to DNA damaging treatment.
Highlights
Despite a huge effort made in the field of targeted anticancer therapy, radiation alone, or in combination with chemotherapeutic drugs, represents one of the most powerful anticancer treatment strategies
We previously showed that leucine zippercontaining alternative reading frame (ARF)-binding protein (LZAP) activates p53 through both ARF-dependent and ARF-independent mechanisms
Downregulation of LZAP remarkably decreased p53 protein in U2OS cells. p53 is important for cellular processes such as cell cycle, differentiation, immune response, metabolism, DNA repair and senescence, and is a potent inducer of apoptosis; p53 protein levels are tightly regulated by multiple mechanisms.[36,37]
Summary
Despite a huge effort made in the field of targeted anticancer therapy, radiation alone, or in combination with chemotherapeutic drugs, represents one of the most powerful anticancer treatment strategies. Mutations in the TP53 gene are found in ~ 50% of all human tumors (in some types of cancer, including head and neck malignancy, the frequency of TP53 mutations is about 90%) and are often associated with poor prognosis.[10,11,12,13] An exclusive feature of the TP53 gene, distinguishing it from other tumor suppressors, is the type of cancer-related genetic alterations, with the majority (480%) of them being missense point mutations resulting in the accumulation of stable mutant protein that has lost its original wild-type activity in the nucleus of tumor cells.[14,15,16,17] Many p53 mutations convey oncogenic activity that increases resistance to radiation and DNA damaging therapy, suggesting downregulation and/or inhibition of mutant p53 (mtp53) as a therapeutic strategy to enhance response to conventional chemotherapeutic drugs or radiation.[14,16,18,19,20,21,22,23] Much effort has been applied toward restoring wild-type p53 functions in mutant p53-expressing cells;[24,25,26,27] temporal decrease of both mutant (present in cancer cells) and wild-type (expressed in normal surrounding cells) p53 has not been extensively addressed. The strategy of simultaneous downregulation of mutant and wild-type p53 should decrease the resistance of tumors with mutant p53 to radiation and chemotherapy, while simultaneously protecting normal tissues from severe side effects
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