Inhibition of p53 and/or AKT as a new therapeutic approach specifically targeting ALT cancers

While the majority of all human cancers counteract telomere shortening by expressing telomerase, ~15% of all cancers maintain telomere length by a telomerase-independent mechanism known as alternative lengthening of telomeres (ALT). Here, we show that high load of intrinsic DNA damage is present in ALT cancer cells, leading to apoptosis stress by activating p53-independent, but JNK/c-Myc-dependent apoptotic pathway. Notably, ALT cells expressing wild-type p53 show much lower apoptosis than p53-deficient ALT cells. Mechanistically, we find that intrinsic DNA damage in ALT cells induces low level of p53 that is insufficient to initiate the transcription of apoptosis-related genes, but is sufficient to stimulate the expression of key components of mTORC2 (mTOR and Rictor), which in turn leads to phosphorylation of AKT. Activated AKT (p-AKT) thereby stimulates downstream anti-apoptotic events. Therefore, p53 and AKT are the key factors that suppress spontaneous apoptosis in ALT cells. Indeed, inhibition of p53 or AKT selectively induces rapid death of ALT cells in vitro, and p53 inhibitor severely suppresses the growth of ALT-cell xenograft tumors in mice. These findings reveal a previously unrecognized function of p53 in anti-apoptosis and identify that the inhibition of p53 or AKT has a potential as therapeutics for specifically targeting ALT cancers.

Comparison of the clinical efficacy between simple vertebral canal decompression and decompression plus laminoplasty / 中南大学学报(医学版)

OBJECTIVE@#To observe the clinical efficacy of the simple expansion of the spinal canal decompression, decompression plus hydroxyapatite/polyamide artificial lamina reconstruction, and decompression plus titanium mesh reconstruction in the treatment of spinal canal stenosi.@*METHODS@#A total of 39 patients with lumbar spinal stenosis (with or without disc herniation, spondylolisthesis less than I degree), who received therapy of surgery from January, 2011 to January, 2012, were retrospectively analyzed. All patients were divided into 3 groups: a laminectomy surgery alone group (group A, n=15), a decompression plus hydroxyapatite/polyamide artificial lamina reconstruction group (group B, n=14), and a laminectomy decompression plus reconstruction with titanium mesh group (group C, n=10). Intraoperative situation, the postoperative excellent rate and JOA score were analyzed.@*RESULTS@#The duration and blood loss in surgery in group A was much less than that in the group B and C (P0.05). Twelve months after the surgery, the group B and C showed advantage over the group A (P0.05); the group B and C showed advantage over the group A in 12 months after the operation (P<0.05). No serious complications were related to the surgery in the 3 groups. Imaging changes were not significant difference.@*CONCLUSION@#The decompression plus hydroxyapatite/polyamide artificial lamina reconstruction and the decompression plus titanium mesh reconstruction show advantages in long-term effect over the simple vertebral canal decompression.