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Translational Science

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Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy marked by early metastasis, dense desmoplastic stroma, and profound resistance to conventional therapies. Despite the development of combination regimens such as gemcitabine and FOLFIRINOX, outcomes remain dismal, with median survival under one year for metastatic cases. This underscores the urgent need for novel therapeutic approaches that target multiple pathways simultaneously. T-cell protein tyrosine phosphatase (TC-PTP) is one of nonreceptor PTPs that negatively regulates oncogenic signaling pathways, particularly STAT3 and AKT, both of which are constitutively active in many solid tumors. Cordycepin, a nucleoside analogue derived from Cordyceps militaris, has demonstrated anticancer effects via inhibition of proliferation, induction of apoptosis, and suppression of metastasis. In this study, we investigate the potential synergistic effects between TC-PTP and cordycepin in human pancreatic cancer cells.

Methods: We established TC-PTP-deficient PANC1 cell lines by lentiviral transduction with shRNA constructs specific for human TC-PTP (PTPN2). Cell viability was assessed using CCK-8 assay. Briefly, both TC-PTP control and TCPTP deficient cells were cultured in DMEM with 10% FBS and 1% penicillin-streptomycin and plated at a density of 10×10⁴ cells/well in 96-well plates. Following overnight incubation, cells were treated with different concentrations of cordycepin and incubated for 72 hours. Absorbance was measured at 450 nm and 690 nm using a microplate reader. Each condition was repeated across three biological replicates. T-tests were used to assess differences in sensitivity between groups. p-values < 0.05 were considered statistically significant.

Results: TC-PTP control PANC1cells exhibited a clear dose-dependent reduction in cell viability after cordycepin treatment. TC-PTP deficient cells, in contrast, showed attenuated response, suggesting TC-PTP enhances cordycepin-induced sensitivity. The most effective responses were observed at concentrations between 500 and 1000 μM of cordycepin. These findings align with the proposed mechanism that TC-PTP-mediated downregulation of oncogenic signaling pathways enhances apoptotic effects of cordycepin.

Conclusions: This dual-targeting strategy—modulating intracellular signaling via TC-PTP while impairing RNA synthesis via cordycepin—presents a compelling approach for overcoming therapeutic resistance in PDAC. The combination leverages two mechanisms, potentially slowing resistance development driven by pathway redundancy. Given both agents’ favorable origin (endogenous and natural), this strategy may reduce systemic toxicity compared to traditional regimens.

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Poster

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TC-PTP enhances cordycepin-induced apoptosis in human pancreatic cancer cells

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy marked by early metastasis, dense desmoplastic stroma, and profound resistance to conventional therapies. Despite the development of combination regimens such as gemcitabine and FOLFIRINOX, outcomes remain dismal, with median survival under one year for metastatic cases. This underscores the urgent need for novel therapeutic approaches that target multiple pathways simultaneously. T-cell protein tyrosine phosphatase (TC-PTP) is one of nonreceptor PTPs that negatively regulates oncogenic signaling pathways, particularly STAT3 and AKT, both of which are constitutively active in many solid tumors. Cordycepin, a nucleoside analogue derived from Cordyceps militaris, has demonstrated anticancer effects via inhibition of proliferation, induction of apoptosis, and suppression of metastasis. In this study, we investigate the potential synergistic effects between TC-PTP and cordycepin in human pancreatic cancer cells.

Methods: We established TC-PTP-deficient PANC1 cell lines by lentiviral transduction with shRNA constructs specific for human TC-PTP (PTPN2). Cell viability was assessed using CCK-8 assay. Briefly, both TC-PTP control and TCPTP deficient cells were cultured in DMEM with 10% FBS and 1% penicillin-streptomycin and plated at a density of 10×10⁴ cells/well in 96-well plates. Following overnight incubation, cells were treated with different concentrations of cordycepin and incubated for 72 hours. Absorbance was measured at 450 nm and 690 nm using a microplate reader. Each condition was repeated across three biological replicates. T-tests were used to assess differences in sensitivity between groups. p-values < 0.05 were considered statistically significant.

Results: TC-PTP control PANC1cells exhibited a clear dose-dependent reduction in cell viability after cordycepin treatment. TC-PTP deficient cells, in contrast, showed attenuated response, suggesting TC-PTP enhances cordycepin-induced sensitivity. The most effective responses were observed at concentrations between 500 and 1000 μM of cordycepin. These findings align with the proposed mechanism that TC-PTP-mediated downregulation of oncogenic signaling pathways enhances apoptotic effects of cordycepin.

Conclusions: This dual-targeting strategy—modulating intracellular signaling via TC-PTP while impairing RNA synthesis via cordycepin—presents a compelling approach for overcoming therapeutic resistance in PDAC. The combination leverages two mechanisms, potentially slowing resistance development driven by pathway redundancy. Given both agents’ favorable origin (endogenous and natural), this strategy may reduce systemic toxicity compared to traditional regimens.

 

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