Abstract
Pancreatic cancer, mostly pancreatic ductal adenocarcinomas (PDAC), is one of the most lethal cancers, with a dismal median survival around 8 months. PDAC is notoriously resistant to chemotherapy. Thus far, numerous attempts using novel targeted therapies and immunotherapies yielded limited clinical benefits for pancreatic cancer patients. It is hoped that delineating the molecular mechanisms underlying drug resistance in pancreatic cancer may provide novel therapeutic options. Using acquired gemcitabine resistant pancreatic cell lines, we revealed an important role of the GLI-SOX2 signaling axis for regulation of gemcitabine sensitivity in vitro and in animal models. Down-regulation of GLI transcriptional factors (GLI1 or GLI2), but not SMO signaling inhibition, reduces tumor sphere formation, a characteristics of tumor initiating cell (TIC). Down-regulation of GLI transcription factors also decreased expression of TIC marker CD24. Similarly, high SOX2 expression is associated with gemcitabine resistance whereas down-regulation of SOX2 sensitizes pancreatic cancer cells to gemcitabine treatment. We further revealed that elevated SOX2 expression is associated with an increase in GLI1 or GLI2 expression. Our ChIP assay revealed that GLI proteins are associated with a putative Gli binding site within the SOX2 promoter, suggesting a more direct regulation of SOX2 by GLI transcription factors. The relevance of our findings to human disease was revealed in human cancer specimens. We found that high SOX2 protein expression is associated with frequent tumor relapse and poor survival in stage II PDAC patients (all of them underwent gemcitabine treatment), indicating that reduced SOX2 expression or down-regulation of GLI transcription factors may be effective in sensitizing pancreatic cancer cells to gemcitabine treatment.
Highlights
These authors contributed : Yanfei Jia, Dongsheng GuElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.The overall survival of cancer patients has significantly improved in the last decade due to the use of multidisciplinary care, improved chemotherapeutic agents, development of novel targeted biologic agents in combination of cancer genomic profiles and improved palliative care services [1]
Molecular characterization of gemcitabine resistant pancreatic cancer cells To understand the molecular basis of gemcitabine resistance, we first characterized two gemcitabine resistant cell lines established from their corresponding parental cell lines Colo357 and BxPC3 following multiple treatments with gemcitabine
We found that the tumors derived Colo357 continued to grow, the tumors derived from the parental Colo357 cells shrunk after gemcitabine treatment (Fig. 1c)
Summary
The overall survival of cancer patients has significantly improved in the last decade due to the use of multidisciplinary care, improved chemotherapeutic agents, development of novel targeted biologic agents in combination of cancer genomic profiles and improved palliative care services [1]. The overall survival of pancreatic cancer patients, patients with pancreatic. Gemcitabine has been the first line therapeutic agent for patients with advanced pancreatic cancer since 1997 [3]. Despite initial responsiveness to gemcitabine, pancreatic cancer eventually develops resistance, and patients succumb to the disease. Gemcitabine is a deoxycytidine analog with specific spectrum of activity and several unique properties. Gemcitabine is known to kill cells with active DNA synthesis by blocking the G1/S transition. Combining albumin-bound paclitaxel with gemcitabine has shown clear therapeutic advantage than gemcitabine alone
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