Abstract 887: Novel role of CD147 in chemoresistance in pancreatic cancer.

Abstract

Abstract Pancreatic cancer is the fourth leading cause of cancer mortality in the U.S. with only a 25% one-year survival rate and 100% mortality rate. No favorable therapeutic strategy has been established in recurrent pancreatic cancer. The cell surface protein CD147 is a glycoprotein and plays a central role in chemoresistance of pancreatic cancer and its upregulation indicates poor prognosis. However, the mechanism by which this protein is involved in pancreatic cancer is still poorly understood. Here we show that knockdown of CD147 in pancreatic cancer cells decelerates tumor growth and sensitizes cells to chemotherapeutic drugs. To identify the mechanisms involved in the slow growth, we screened several genes using a luciferase method. We found that knockdown of CD147 leads to decreased transcription of several genes involved in cancer progression such as telomerase and VEGFC. Knockdown of CD147 leads to high sensitivity of pancreatic cancer cells to chemotherapeutics such as gemcitabine and doxorubicin. Interestingly, the metastatic cell line, L3.6pL, is more sensitive to both chemotherapeutic drugs than the non-metastatic cell line, Panc-1. CD147 knockdown also leads to less drug efflux than control as detected by rhodamine assay. Our hypothesis is that CD147 may interact and block some membrane transporters, which lead to an increase of intracellular drug and therefore to chemosensitivity. We analyzed the transcriptional activity of several membrane transporters including ABCC5, ABCC10 and ABCA2. We found that there is a decrease in their transcription levels of approximately 50% compared to the control. This may suggest that CD147 is involved in drug transport through the cytoplasmic membrane. We have also determined that depleting CD147 leads to an increase of sensitivity in pancreatic cancer cells to chemotherapeutic drugs such as doxorubicin and gemcitabine. Gemcitabine can create DNA damage such as double stand breaks in cells, followed rapidly by histone H2AX phosphorylation (𝛄H2AX), with foci observed within the first minute. Using CD147 knockdown cells, we showed that knockdown of CD147 leads to the depletion of H2AX phosphorylation and to an increase of apoptosis, in agreement with high drug accumulation. We found high ROS levels in these cells as measured by the DCF using flow cytometry. This can explain an increase of apoptosis in cells with CD147 knockdown. Our results indicate that CD147 acts to enhance tumor growth in several ways and contributes to chemoresistance in pancreatic cancer. We explored the mechanism of action of CD147, which can be a potential novel therapeutic target in pancreatic cancer. Citation Format: Karim Bahmed, Michael Holliday, Agnieszka Kendrick, Elan Eisenmesser. Novel role of CD147 in chemoresistance in pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 887. doi:10.1158/1538-7445.AM2013-887