Cyclin dependent kinase 5 decreases in gastric cancer and its nuclear accumulation suppresses gastric tumorigenesis Running Head: CDK5 suppresses gastric tumorigenesis

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Cyclin dependent kinases (CDKs) contribute to tumor development by initiating unscheduled cell division. As an atypical CDK, CDK5 has been traditionally viewed as a functional component in the central nervous system rather than in cell proliferation. Here for the first time, we identify a dramatic reduction of CDK5 expression in gastric tumors and reveal a significant correlation of reduced CDK5 expression with advanced clinical stage and poor survival in gastric cancer patients. Moreover, we demonstrate that it is the nuclear localization of CDK5, rather than CDK5 activity, suppress tumorigenic progression in gastric cancer. Our findings provide a basis for future work delineating pharmacological modulation of CDK5 nuclear accumulation in gastric cancer, and suggest that CDK5 may have a role in inhibiting cell cycle progression. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract: Purpose: As a cyclin–independent atypical CDK, the role of CDK5 in regulating cell proliferation in gastric cancer remains unknown. Experimental Design: Expression of CDK5 in gastric tumor and paired adjacent noncancerous tissues from 437 patients were measured by Western blotting, immunohistochemistry, and real-time PCR. The subcelluar translocation of CDK5 was monitored during gastric cancer cell proliferation. The role of nuclear CDK5 in gastric cancer tumorigenic proliferation and ex vivo xenografts was explored. Furthermore, by screening for compounds in the PubChem database that disrupt CDK5 association with its nuclear export facilitator, we identified a small molecular (NS-0011) that inhibits gastric cancer cell growth. Results: CDK5 level was significantly decreased in the majority of gastric tumor tissues, and the reduction of CDK5 correlated with the severity of gastric cancer based on tumor and lymph node metastasis and patient 5-year fatality rate. Nuclear localization of CDK5 was found to be significantly decreased in tumor tissues and gastric cancer cell lines, whereas exogenously expression of nucleus-targeted CDK5 inhibited the proliferation and xenograft implantation of gastric cancer cells. Treatment with the small molecule NS-0011, which increases CDK5 accumulation in the nucleus, suppressed both cancer cell proliferation and xenograft tumorigenesis. Conclusion: Our results suggest that low CDK5 expression is associated with poor overall survival in patients with gastric cancer, and nuclear accumulation of CDK5 inhibits the proliferation and tumorigenicity of human gastric cancer cells. Author manuscripts have been peer reviewed and accepted for publication but have not yet been …