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Identification of chemoresistance-related mRNAs based on gemcitabine-resistant pancreatic cancer cell lines.

ABSTRACT: Gemcitabine (GEM) alone and GEM-based chemotherapy are the preferred regimens for treating advanced unresectable and metastatic pancreatic cancer (PC). However, these treatments have limited efficacy due to acquired resistance of cancer cells to chemotherapy, the mechanisms of which are not fully understood. In this study, we established two stable multidrug-resistant cell lines, BxPC-3-GR and CFPAC-1-GR, from their corresponding parental cells through exposure to GEM following a stepwise incremental dosing strategy. The GEM IC50 values of BxPC-3-GR and CFPAC-1-GR increased 112-fold and 210-fold, respectively, compared to parental cell lines. In vitro and in vivo experiments confirmed that both GEM-resistant cell subgroups declined in proliferative capacity, but were more resistant to GEM. Unlike CFPAC-1-GR, BxPC-3-GR exhibited enhanced migratory and invasive properties compared with BxPC-3 in vitro. We also compared differentially expressed mRNA profiles between parental and GEM-resistant cells using transcriptome sequencing. RRM1, STIM1, and TRIM21 were significantly upregulated in both GEM-resistant cell lines and confirmed to be associated with the degree of GEM resistance by quantitative reverse-transcription polymerase chain reaction and western blot analysis. These three genes were more highly expressed in PC tissues and potentially regarded as prognostic biomarkers through database mining. Thus, our findings provide chemo-resistant cell models to better understand the underlying mechanisms of chemoresistance, and to explore potential biomarkers for GEM response in PC patients.

SUBMITTER: Zhou J

PROVIDER: S-EPMC6997050 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Identification of chemoresistance-related mRNAs based on gemcitabine-resistant pancreatic cancer cell lines.

Zhou Jiarong J Zhang Linshi L Zheng Huilin H Ge Wenhao W Huang Yu Y Yan Yingcai Y Zhou Xiaohu X Zhu Wei W Kong Yang Y Ding Yuan Y Wang Weilin W

Cancer medicine 20191211 3

Gemcitabine (GEM) alone and GEM-based chemotherapy are the preferred regimens for treating advanced unresectable and metastatic pancreatic cancer (PC). However, these treatments have limited efficacy due to acquired resistance of cancer cells to chemotherapy, the mechanisms of which are not fully understood. In this study, we established two stable multidrug-resistant cell lines, BxPC-3-GR and CFPAC-1-GR, from their corresponding parental cells through exposure to GEM following a stepwise increm ...[more]

PMID: 31823522

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Project description:BACKGROUND: One of the major reasons for poor prognosis of pancreatic cancer is its high resistance to currently available chemotherapeutic agents. In recent years, focal adhesion kinase (FAK), a central molecule in extracellular matrix (ECM)/integrin-mediated signaling, has been thought to be a key determinant of chemoresistance in cancer cells. In this study, we aimed to determine the roles of FAK phosphorylation in the intrinsic chemoresistance of pancreatic cancer cell lines. RESULTS: Our results showed that, the level of constitutive phosphorylation of FAK at Tyr397 correlated with the extent of intrinsic resistance to Gemcitabine (Gem) in four pancreatic cancer cell lines. Moreover, in Panc-1 cells, which had high expression of pFAK, specific inhibition of constitutive FAK phosphorylation by either RNAi or FRNK overexpression decreased the phosphorylation of Akt, reduced the levels of survivin expression and Bad phosphorylation at Ser136 and increased Gem-induced cytotoxicity and apoptosis. However, in AsPC-1 cells with a low level of pFAK, neither FAK RNAi nor FRNK overexpression affected Gem-induced cell apoptosis. We further found that laminin (LN) induced FAK and Akt phosphorylation in a time-dependent manner, increased the levels of survivin and pBad (pS136) and decreased Gem-induced cytotoxicity and apoptosis in AsPC-1 cells; Specific inhibition of LN-induced FAK phosphorylation by either FAK RNAi or FRNK overexpression suppressed the effects of LN on AsPC-1 cells. Moreover, inhibition of constitutive FAK phosphorylation in Panc-1 cells and LN-induced FAK phosphorylation in AsPC-1 cells by a novel and more specific FAK phosphorylation inhibitor PF-573,228 showed similar results with those of FAK phosphorylation inhibition by FAK RNAi or FRNK overexpression. CONCLUSIONS: In conclusion, our research demonstrates for the first time that both constitutive and LN-induced FAK phosphorylation contribute to increased intrinsic chemoresistance to Gem in pancreatic cancer cell lines and these effects are partly due to the regulation of Akt and Bad phosphorylation and survivin expression. Development of selective FAK phosphorylation inhibitors may be a promising way to enhance chemosensitivity in pancreatic cancer.

Dataset Information

Identification of chemoresistance-related mRNAs based on gemcitabine-resistant pancreatic cancer cell lines.

Publications

Identification of chemoresistance-related mRNAs based on gemcitabine-resistant pancreatic cancer cell lines.

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