Chemotherapeutic regimens selleck kinase inhibitor utilized clinically for patients with stage III CRC typically include a fluoropyrimidine and OXP, whereas a fluoropyrimidine backbone with OXP or CPT is given to patients with stage IV disease. Our data demonstrated that cell survival signaling triggered by IL 6 in HCT116 cells is mitigated by OXP and CPT. Western blot analysis of HCT116 cells treated with IL 6 and OXP demonstrated a reduction in both pRKIP and pY705STAT3 back to basal levels. The same observations were made using IL 6 combined with CPT. Since the HCT116 cells are not representative of a particular stage of colon cancer, the fact that both OXP and CPT caused similar reductions in phosphorylation suggests that they trigger similar cellular mechanisms while causing apoptosis.
These results support an alternative anti tumor activity mechanism of action for these compounds. Our data uncovered another mechanism by which an irinotecan analog CPT is able to inhibit IL 6 mediated STAT3 phosphorylation. STAT3 cannot bind to the gp130 subunit of the IL 6 receptor until IL 6 binds to the extracellular side of the receptor. Treatment with CPT disrupted the binding if STAT3 to gp130 in the presence of IL 6. This inhibition of binding explains why STAT3 was no longer phosphorylated upon IL 6 stimula tion in the presence of CPT. In order to further investigate the involvement of the JAK STAT pathway in enhancing colon cancer cell survival and the mechanism of RKIP phosphorylation, we examined whether JAK 1 and 2 overexpression could stimulate STAT3 activation and thereby negate the inhibitory effects of CPT.
JAK 1 and 2 caused an increase in STAT3 transcription, which was associated with an increase in pRKIP. Treatment with CPT was able to significantly reduce the levels of STAT3 transcription activity and the levels of pRKIP. Therefore, the versatility of camptothecin as a front line chemotherapy agent is increased because, in addition to inhibiting topoisomerase I, CPT is able to enhance apoptosis of cancer cells by disrupting survival signaling of the JAK STAT pathway at the receptor level. Conclusions In summary, this study examines for the first time, the expression profile of RKIP, pRKIP and STAT3 in Stage II colon cancer. Our results strongly suggest the role of pRKIP and STAT3 in the provision of clinically prognostic and therapeutic information.
Our data indicate that the current treatment for colon cancer, FOLFOX and FOLFIRI, are both effective in reducing pRKIP levels in vitro. There fore, examining a larger cohort of patients, in the future, will provide additional data for the assessment of pRKIP and STAT3 for the risk for recurrence of colon cancer. Consent Written informed consent was obtained from the patients for the publication inhibitor Vismodegib of this report and any accompanying images.