Abstract
BackgroundPaclitaxel is a first-line chemotherapy drug for pancreatic, ovarian, endometrial cancers and other malignancies. However, its efficacy is often compromised by decreased cell sensitivity or the development of resistance. Human epididymis protein 4 (HE4) is highly expressed in gynecologic and pancreatic cancer tissues, and its serum levels are used for patient triage and assistant diagnosis of gynecologic cancers. Previous studies have shown that HE4 overexpression could promote cancer cell proliferation and the growth of tumor xenografts, which suggests its potential involvement in cancer chemosensitivity.MethodsTwo pancreatic cancer cell lines, Capan-1 and Suit-2, were transiently transfected with an HE4 overexpression plasmid, and transfected cells were treated with paclitaxel. S-phase cells were labeled using BrdU, and cell positivity rates were determined by counting BrdU-positive cells. Following HE4 overexpression and/or drug treatment, a western blotting analysis was performed to determine the protein alterations of PCNA and p21, two important cell cycle regulators.ResultsHE4 overexpression not only promoted the proliferation of the Capan-1 pancreatic cells, but also significantly decreased cell sensitivity to paclitaxel. Results from western blotting showed that paclitaxel inhibited cell proliferation by decreasing the expression of PCNA and increasing the expression of p21. Data analysis indicated interactive actions between HE4 function and paclitaxel effects, both converging to cell cycle regulation.ConclusionThese findings suggest that HE4 could be a potential therapeutic target for the sensitization of pancreatic cancer cells to paclitaxel treatment. HE4 expression levels may be used to predict the sensitivity of pancreatic cancer patients to paclitaxel.
Highlights
Paclitaxel is a first-line chemotherapy drug for pancreatic, ovarian, endometrial cancers and other malignancies
Since the current study dealt with two factors from different angles—a chemotherapy drug, and a cellular factor Human epididymis protein 4 (HE4)—to delineate their individual effects and the potential interaction, all the experiments were designed to include four groups: (1) Control without Pac treatment and HE4 expression manipulation
Consistent with these reports, data from the current study indicate that HE4 can promote the proliferation of pancreatic cancer cells as well
Summary
Paclitaxel is a first-line chemotherapy drug for pancreatic, ovarian, endometrial cancers and other malignancies. Drug resistance continues to be a major impediment for PDAC treatment [11]. Several potential mechanisms dictate drug sensitivity or the development of resistance to chemotherapy: (1) The intracellular concentrations of small, hydrophobic, nonpolar drug molecules can be reduced by cell membrane pumps through efflux mechanisms. It is well recognized that the overexpression of the P-glycoprotein (MDR1) leads to increased drug resistance [12, 13]. (4) Expression alterations or post-translation modifications of key cell cycle or apoptosis regulators could lead to changes in cell sensitivity to drugs targeting these pathways. A wide range of factors participate in cell cycle/apoptosis modulation, and identification of such factors is required for a better understanding of chemoresistance mechanisms and the improvement of PDAC treatment
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