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研究摘要：
Pancreatic cancer is the fourth leading cause of cancer deaths in the world and one of the top 10 cancer-related deaths in Taiwan. The reports indicated the survival outcome for pancreatic cancer patients in five year is less than 8% and the median disease-free survival is about 12.5 months in USA. The poor survival of pancreatic cancer is due to early tumor metastasis, the lack of feasible detection markers at early stage of diseases, and the presence of high resistance to chemo/radiotherapy. Gemcitabine (GEM, 2’,2’-difluorodeoxycytidine), is a difluoro analog of deoxycytidine which is used as standard treatment of chemotherapy in pancreatic cancer. However, its efficacy is around 20–30% and most of patients present the acquire resistance to gemcitabine, but the mechanisms still unclear. In order to improve the effectiveness of the clinical treatments, it is urgently needing to further clarify the underlying mechanism of gemcitabine resistance of pancreatic cancer and to develop new strategy for treatment.
Emerging evidences also reveal a strong connection between dysregulated metabolism and cancer progression, suggesting that metabolic switch might play a critical role in cancer growth, progression and could help overcome resistance to chemotherapy. Current studies indicate that various human cancers showed higher levels of proline cycle controlling enzymes, comparing to normal tissues. Because of higher energy need in cancer cell, the activation of proline cycle triggers the pentose phosphate pathway (PPP) and nucleotide biosynthesis process. In the oxidative arm of proline cycle, the cancer cells can rapidly proliferate by using G6p-pyruvate metabolic pathway depending on the metabolic context, when glucose is readily available. Lactate dehydrogenase A catalyzes the conversion of pyruvate and NADH to lactate and NAD+, the final step of the glycolytic pathway, and has important roles in tumor progression. On the other hand, the proline-cycle can also increase the activity of the oxidative pentose phosphate pathway, which in turn generates precursors for nucleotide biosynthesis which is required for DNA and RNA production. Given the roles of proline cycle in cancer cells, it has been hypothesis that glucose metabolism changes in tumors may be driven by alterations in the expression levels or activity of proline cycle. Moreover, elevation of proline cycle-associated enzymes (such as Pyrroline-5-Carboxylate Reductase 1, PYCR1) has regarded as a hallmark in many tumors, used as a selectively target for cancer therapy and displayed a poor prognosis in several human malignancies. The expression levels of proline-cycle directly influence the Warburg effect, amino acids metabolism, DNA biosynthesis and energy obtain and consumption (oxidation and reduction). Therefore, to modulate proline metabolism has considered as a potential cancer therapy target.
Furthermore, it has been reported that regulation of proline metabolism via transcriptional and post-translational regulation by cancer-associated factor, c-myc, in cancer. Therefore, understanding mechanism of proline cycle involves in the gemcitabine resistance, cancer stemness and progression of PDAC has benefit to develop new strategy for treatment.
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