p8 Is a New Target of Gemcitabine in Pancreatic Cancer Cells

Abstract

Gemcitabine is the only available chemotherapeutic treatment of pancreatic cancers. It is, however, moderately effective, showing a tumor response rate of only 12%. The aim of this work was to identify new pathways involved in the resistance of pancreatic cancer cells to gemcitabine, in the hope of developing new adjuvant strategies to enhance its therapeutic efficacy. Comparison of gene expression patterns of five human pancreatic cancer cell lines showing different degrees of resistance to gemcitabine revealed specific overexpression of several genes in the most resistant. One of them encoded the antiapoptotic p8 protein.We found that (a) knocking down p8 expression in gemcitabine-resistant cells promoted cell death and increased caspase-3 activity; (b) forced overexpression of p8 in gemcitabine-sensitive cells increased their resistance to gemcitabine-induced apoptosis; and (c) gemcitabine down-regulated p8 mRNA expression. These results suggest that, in pancreatic cancer cells, a large part of gemcitabine-induced apoptosis results from the inhibition of the constitutive antiapoptotic activity of p8. Hence, targeting the p8-associated pathway could be a new adjuvant therapy improving the response of patients with pancreatic cancer to gemcitabine treatment.Pancreatic cancer is the fifth most common cause of death by cancer in the Western world (1). The anatomic localization of the pancreas and the lack of specificity of the symptoms result in a complex and delayed diagnosis. Therefore, at the time of detection, 85% of patients show metastatic infiltration in proximal lymph nodes, liver, or lungs. The current 5-year survival rate is f3% and only surgical resection (possible in 15% of the cases) can increase survival rate to 20%.

Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug

“…Precise mechanisms for pancreatic cancer cell resistance to gemcitabine are not well understood, and gene expression profiles in correlation with cell sensitivity have been proposed. These multiple genes encode for proteins involved both in the regulation of survival or apoptotic machinery, including Src tyrosine kinase (29), c-Met tyrosine kinase receptor (30), protein kinase B/ Akt and NF-κB (31), focal adhesion kinase (32), integrinlinked kinase (33), inhibitor of apoptosis proteins (34), antiapoptotic Bcl-2 or Bcl-xL (35), and p8 proteins (36), or in phenotypic alterations including epithelial-to-mesenchymal transition and reexpression of stem cell markers (30). Nucleoside transporters, including hENT1, and cellular enzymes, including dCK, RRM1, and RRM2, which regulate gemcitabine transport and metabolism, respectively, are also important determinants for gemcitabine cytotoxicity and clinical efficacy in pancreatic cancer (37)(38)(39)(40).…”

p8 attenuates the apoptosis induced by dihydroartemisinin in cancer cells through promoting autophagy

“…9 P8 participates in a wide range of biological functions in tumorigenesis, including anti-inflammatory, 10 cell cycle regulation, 11 autophagy, 12 and apoptosis inhibition. 13 Accumulating studies have shown that p8 is overexpressed in various cancer cells including pancreatic cancer, 14 colorectal carcinoma 15 and brain tumors. 16 Moreover, it has been reported that p8 is involved in the resistance of cancer cells to gemcitabine and adriamycin.…”

“…16 Moreover, it has been reported that p8 is involved in the resistance of cancer cells to gemcitabine and adriamycin. 14,17 Therefore, p8 might be a new drug-targetable gene in preventing the progression and metastasis of cancer. 18 In this study, we discovered DHA upregulates p8 remarkably in several cancer cells, and we sought to find out what role p8 plays in the antiproliferative actions of DHA in cancer cells.…”

Candidate of metastasis 1 regulates in vitro growth and invasion of bladder cancer cells

“…whether it is stimulating or inhibiting may vary in different malignancies. COM1 has been found to aid the establishment of metastasis and to play a key role in the progression of malignancies of breast (1,(5)(6)(7)13), thyroid (4,13,14), central nervous system (15) and pancreas (3,16,17). COM1 has been implicated in inducing chemoresistance in pancreatic and breast cancer cells, protecting them from apoptosis and making tumour cells genetically unstable (17).…”