Refine
Document Type
- Article (2)
Language
- English (2)
Has Fulltext
- yes (2)
Is part of the Bibliography
- no (2)
Keywords
- BRUCE (1)
- LIVIN (1)
- Nek1 (1)
- Survivin (1)
- TP53 (1)
- XIAP (1)
- cIAP1/2 (1)
- cervical cancer (1)
- colorectal cancer (1)
- colorectal carcinoma (1)
Institute
- Medizin (2)
Despite recent advances in the treatment of colorectal cancer (CRC), patient’s individual response and clinical follow-up vary considerably with tumor intrinsic factors to contribute to an enhanced malignancy and therapy resistance. Among these markers, upregulation of members of the inhibitor of apoptosis protein (IAP) family effects on tumorigenesis and radiation- and chemo-resistance by multiple pathways, covering a hampered induction of apoptosis/autophagy, regulation of cell cycle progression and DNA damage response. These mechanisms are tightly controlled by the tumor suppressor p53 and thus transcriptional and post-translational regulation of IAPs by p53 is expected to occur in malignant cells. By this, cellular IAP1/2, X-linked IAP, Survivin, BRUCE and LIVIN expression/activity, as well as their intracellular localization is controlled by p53 in a direct or indirect manner via modulating a multitude of mechanisms. These cover, among others, transcriptional repression and the signal transducer and activator of transcription (STAT)3 pathway. In addition, p53 mutations contribute to deregulated IAP expression and resistance to therapy. This review aims at highlighting the mechanistic and clinical importance of IAP regulation by p53 in CRC and describing potential therapeutic strategies based on this interrelationship.
NIMA (never-in-mitosis gene A)-related kinase 1 (Nek1) is shown to impact on different cellular pathways such as DNA repair, checkpoint activation, and apoptosis. Its role as a molecular target for radiation sensitization of malignant cells, however, remains elusive. Stably transduced doxycycline (Dox)-inducible Nek1 shRNA HeLa cervix and siRNA-transfected HCT-15 colorectal carcinoma cells were irradiated in vitro and 3D clonogenic radiation survival, residual DNA damage, cell cycle distribution, and apoptosis were analyzed. Nek1 knockdown (KD) sensitized both cell lines to ionizing radiation following a single dose irradiation and more pronounced in combination with a 6 h fractionation (3 × 2 Gy) regime. For preclinical analyses we focused on cervical cancer. Nek1 shRNA HeLa cells were grafted into NOD/SCID/IL-2Rγc−/− (NSG) mice and Nek1 KD was induced by Dox-infused drinking water resulting in a significant cytostatic effect if combined with a 6 h fractionation (3 × 2 Gy) regime. In addition, we correlated Nek1 expression in biopsies of patients with cervical cancer with histopathological parameters and clinical follow-up. Our results indicate that elevated levels of Nek1 were associated with an increased rate of local or distant failure, as well as with impaired cancer-specific and overall survival in univariate analyses and for most endpoints in multivariable analyses. Finally, findings from The Cancer Genome Atlas (TCGA) validation cohort confirmed a significant association of high Nek1 expression with a reduced disease-free survival. In conclusion, we consider Nek1 to represent a novel biomarker and potential therapeutic target for drug development in the context of optimized fractionation intervals.