Suppression of Wnt/β-catenin and RAS/ERK pathways provides a therapeutic strategy for gemcitabine-resistant pancreatic cancer

Won Ji Ryu; Gyoonhee Han; Soung Hoon Lee; Kang Yell Choi

doi:10.1016/j.bbrc.2021.02.076

Suppression of Wnt/β-catenin and RAS/ERK pathways provides a therapeutic strategy for gemcitabine-resistant pancreatic cancer

Won Ji Ryu, Gyoonhee Han, Soung Hoon Lee, Kang Yell Choi

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

Pancreatic cancer is a major malignant tumor without an effective treatment. KRAS mutations occur in 90% of the pancreatic cancer patients and are a major obstacle for treatment of pancreatic cancer. Pancreatic cancer patients have been treated with limited chemotherapeutic agents such as gemcitabine. However, patients often develop resistance to gemcitabine that is attributed to KRAS mutations. Gemcitabine treatment activates both the Wnt/β-catenin and RAS/ERK pathways. These signaling pathways are also activated in the gemcitabine-resistant pancreatic cancer cell lines, suggesting that they play an important role in gemcitabine resistance in pancreatic cancer. The gemcitabine-resistant cell lines show enhanced migratory and invasive capabilities than their parental lines. Therefore, we investigated the effects of a small molecule, KYA1797K that degrades both β-catenin and RAS, on pancreatic cancer. KYA1797K decreased the expression level of both β-catenin and KRAS in pancreatic cancer cell lines expressing either wild-type or mutant KRAS. It also suppressed migration and invasion of gemcitabine-resistant and parental pancreatic cancer cells. Overall, we demonstrated that inhibiting the Wnt/β-catenin and RAS/ERK pathways by destabilizing β-catenin and RAS could be a therapeutic approach to overcome gemcitabine resistance in pancreatic cancer.

Original language	English
Pages (from-to)	40-46
Number of pages	7
Journal	Biochemical and Biophysical Research Communications
Volume	549
DOIs	https://doi.org/10.1016/j.bbrc.2021.02.076
Publication status	Published - 2021 Apr 16

Bibliographical note

Funding Information:
We thank S.Y Song and Professor J.S Noh for providing the pancreatic cancer cell lines. This study was supported by the Brain Korea 21 ( BK21 ) Program and the National Research Foundation of Korea (NRF) grant funded by the Korean Government ( MSIP ) ( 2019R1A2C3002751 , 2020M3E5E2040018 ). W.-J. Ryu was supported by the Global Ph.D Fellowship Program through the NRF, funded by the Ministry of Education ( 2015H1A2A1034548 ).

Publisher Copyright:
© 2021 The Authors

All Science Journal Classification (ASJC) codes

Biophysics
Biochemistry
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbrc.2021.02.076

Cite this

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title = "Suppression of Wnt/β-catenin and RAS/ERK pathways provides a therapeutic strategy for gemcitabine-resistant pancreatic cancer",

abstract = "Pancreatic cancer is a major malignant tumor without an effective treatment. KRAS mutations occur in 90% of the pancreatic cancer patients and are a major obstacle for treatment of pancreatic cancer. Pancreatic cancer patients have been treated with limited chemotherapeutic agents such as gemcitabine. However, patients often develop resistance to gemcitabine that is attributed to KRAS mutations. Gemcitabine treatment activates both the Wnt/β-catenin and RAS/ERK pathways. These signaling pathways are also activated in the gemcitabine-resistant pancreatic cancer cell lines, suggesting that they play an important role in gemcitabine resistance in pancreatic cancer. The gemcitabine-resistant cell lines show enhanced migratory and invasive capabilities than their parental lines. Therefore, we investigated the effects of a small molecule, KYA1797K that degrades both β-catenin and RAS, on pancreatic cancer. KYA1797K decreased the expression level of both β-catenin and KRAS in pancreatic cancer cell lines expressing either wild-type or mutant KRAS. It also suppressed migration and invasion of gemcitabine-resistant and parental pancreatic cancer cells. Overall, we demonstrated that inhibiting the Wnt/β-catenin and RAS/ERK pathways by destabilizing β-catenin and RAS could be a therapeutic approach to overcome gemcitabine resistance in pancreatic cancer.",

author = "Ryu, {Won Ji} and Gyoonhee Han and Lee, {Soung Hoon} and Choi, {Kang Yell}",

note = "Funding Information: We thank S.Y Song and Professor J.S Noh for providing the pancreatic cancer cell lines. This study was supported by the Brain Korea 21 ( BK21 ) Program and the National Research Foundation of Korea (NRF) grant funded by the Korean Government ( MSIP ) ( 2019R1A2C3002751 , 2020M3E5E2040018 ). W.-J. Ryu was supported by the Global Ph.D Fellowship Program through the NRF, funded by the Ministry of Education ( 2015H1A2A1034548 ). Publisher Copyright: {\textcopyright} 2021 The Authors",

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N1 - Funding Information: We thank S.Y Song and Professor J.S Noh for providing the pancreatic cancer cell lines. This study was supported by the Brain Korea 21 ( BK21 ) Program and the National Research Foundation of Korea (NRF) grant funded by the Korean Government ( MSIP ) ( 2019R1A2C3002751 , 2020M3E5E2040018 ). W.-J. Ryu was supported by the Global Ph.D Fellowship Program through the NRF, funded by the Ministry of Education ( 2015H1A2A1034548 ). Publisher Copyright: © 2021 The Authors

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N2 - Pancreatic cancer is a major malignant tumor without an effective treatment. KRAS mutations occur in 90% of the pancreatic cancer patients and are a major obstacle for treatment of pancreatic cancer. Pancreatic cancer patients have been treated with limited chemotherapeutic agents such as gemcitabine. However, patients often develop resistance to gemcitabine that is attributed to KRAS mutations. Gemcitabine treatment activates both the Wnt/β-catenin and RAS/ERK pathways. These signaling pathways are also activated in the gemcitabine-resistant pancreatic cancer cell lines, suggesting that they play an important role in gemcitabine resistance in pancreatic cancer. The gemcitabine-resistant cell lines show enhanced migratory and invasive capabilities than their parental lines. Therefore, we investigated the effects of a small molecule, KYA1797K that degrades both β-catenin and RAS, on pancreatic cancer. KYA1797K decreased the expression level of both β-catenin and KRAS in pancreatic cancer cell lines expressing either wild-type or mutant KRAS. It also suppressed migration and invasion of gemcitabine-resistant and parental pancreatic cancer cells. Overall, we demonstrated that inhibiting the Wnt/β-catenin and RAS/ERK pathways by destabilizing β-catenin and RAS could be a therapeutic approach to overcome gemcitabine resistance in pancreatic cancer.

AB - Pancreatic cancer is a major malignant tumor without an effective treatment. KRAS mutations occur in 90% of the pancreatic cancer patients and are a major obstacle for treatment of pancreatic cancer. Pancreatic cancer patients have been treated with limited chemotherapeutic agents such as gemcitabine. However, patients often develop resistance to gemcitabine that is attributed to KRAS mutations. Gemcitabine treatment activates both the Wnt/β-catenin and RAS/ERK pathways. These signaling pathways are also activated in the gemcitabine-resistant pancreatic cancer cell lines, suggesting that they play an important role in gemcitabine resistance in pancreatic cancer. The gemcitabine-resistant cell lines show enhanced migratory and invasive capabilities than their parental lines. Therefore, we investigated the effects of a small molecule, KYA1797K that degrades both β-catenin and RAS, on pancreatic cancer. KYA1797K decreased the expression level of both β-catenin and KRAS in pancreatic cancer cell lines expressing either wild-type or mutant KRAS. It also suppressed migration and invasion of gemcitabine-resistant and parental pancreatic cancer cells. Overall, we demonstrated that inhibiting the Wnt/β-catenin and RAS/ERK pathways by destabilizing β-catenin and RAS could be a therapeutic approach to overcome gemcitabine resistance in pancreatic cancer.

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Suppression of Wnt/β-catenin and RAS/ERK pathways provides a therapeutic strategy for gemcitabine-resistant pancreatic cancer

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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