Abstract
Pancreatic cancer has a 5-year survival rate of less than 4%. Despite advances in diagnostic technology, pancreatic cancer continues to be diagnosed at a late and incurable stage. Accurate biomarkers for early diagnosis and to predict treatment response are urgently needed. Since alteration of glucose metabolism is one of the hallmarks of cancer cells, we proposed that pyruvate kinase type M2 (M2PK) and lactate dehydrogenase A (LDHA) enzymes could represent novel diagnostic markers and potential therapeutic targets in pancreatic cancer. In 266 tissue sections from normal pancreas, pancreatic cystic neoplasms, pancreatic intraepithelial neoplasia (PanIN) and cancer, we evaluated the expression of PKM2, LDHA, Ki-67 and CD8+ by immunohistochemistry and correlated these markers with clinicopathological characteristics and patient survival. PKM2 and LDHA expression was also assessed by Western blot in 10 human pancreatic cancer cell lines. PKM2 expression increased progressively from cyst through PanIN to cancer, whereas LDHA was overexpressed throughout the carcinogenic process. All but one cell line showed high expression of both proteins. Patients with strong PKM2 and LDHA expression had significantly worse survival than those with weak PKM2 and/or LDHA expression (7.0 months vs. 27.9 months, respectively, p = 0.003, log rank test). The expression of both PKM2 and LDHA correlated directly with Ki-67 expression, and inversely with intratumoral CD8+ cell count. PKM2 was significantly overexpressed in poorly differentiated tumours and both PKM2 and LDHA were overexpressed in larger tumours. Multivariable analysis showed that combined expression of PKM2 and LDHA was an independent poor prognostic marker for survival. In conclusion, our results demonstrate a high expression pattern of two major glycolytic enzymes during pancreatic carcinogenesis, with increased expression in aggressive tumours and a significant adverse effect on survival.
Highlights
Pancreatic cancer is one of the most common gastrointestinal cancers and the fourth most common cause of cancer-related deaths worldwide [1]
Aerobic glycolysis is a hallmark of cancer cells, with the production of lactate even in the presence of ample amounts of oxygen, a phenomenon known as the Warburg effect [5,6,7]
Pyruvate kinase (PK) is a tightly regulated glycolytic enzyme that catalyses the last step of glycolysis and mediates the transfer of phosphate from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP) to produce pyruvate and energy (ATP) [10,11,12]
Summary
Pancreatic cancer is one of the most common gastrointestinal cancers and the fourth most common cause of cancer-related deaths worldwide [1]. An important advantage of increased glycolysis in tumour cells is production of energy without the consumption of oxygen and glycolytic intermediates, such as amino acids, nucleotides, phospholipids and triglycerides, which are used as macromolecules for the synthesis of structural elements of new cells [5,6,8,9]. PK has four different isoenzymes PKM1, PKM2, PKL and PKR, the expression of which depends on the metabolic response of cells. Both L and M genes encode PK isoenzymes. PKM2 expression can oscillate between the highly active tetrameric isoform and the nearly inactive dimeric isoform, depending on the cellular demand of energy or production of anabolic intermediates for cell proliferation. The tetrameric isoform of PKM2 is predominantly expressed in normal cells, while its dimeric isoform is usually found in tumour cells, the name tumour PKM2 [11,14,19]
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