Inhibition of activated Stat3 reverses drug resistance to chemotherapeutic agents in gastric cancer cells
Abstract
Multidrug resistance is a major obstacle in the treatment of gastric cancer. The underlying mechanisms of this phenomenon have not been well understood. Accumulating evidence indicates that Stat3 plays an important role in tumorigenesis of various primary cancers and cancer cell lines by upregulating cell survival proteins and downregulating tumor suppressors. We propose that the Stat3 pathway is also involved in acquired drug resistance of gastric cancer. To test this hypothesis, we investigated the expression and activation of Stat3 in drug resistant gastric cancer cell lines. Western blotting and real-time reverse transcription-PCR determined that Stat3 and its target genes were overactivated and/or overexpressed in drug resistant cells. Inhibition of Stat3 function resulted in significant decreases in cisplatin resistance and enhanced apoptosis in drug resistant cells. The levels of Stat3 target oncogenes such as Bcl-2 and c-Myc were decreased with DPP, a Stat3 inhibitor, treatment, while the expression of tumor suppressor p53 was increased. Interestingly, the vacuolar ATPase, a proton pump which interferes the uptake of therapeutic drugs, was down regulated by Stat3 inhibition. In conclusion, these data supported the hypothesis that interruption of Stat3 signaling could reverse resistance to chemotherapy agents in human gastric cancer cells.
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STAT3 is implicated in chemotherapy resistance; there is a strong correlation between STAT3 activation and chemoresistance, and STAT3 inhibition restores sensitivity of tumors to chemotherapeutic drugs.
“STAT3 has been implicated in chemotherapy resistance; there is a strong correlation between STAT3 activation and chemoresistance, and STAT3 inhibition has been shown to restore sensitivity of tumors to chemotherapeutic drugs”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Huang et al., 2012
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Targeting multidrug resistance in cancer
Szakács, G., Paterson, J. K., Ludwig, J. A., Booth-Genthe, C., & Gottesman, M. M. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd1984 · Cited by 3,609 · see citing works
Analysis of Signal Transducer and Activator of Transcription 3 (Stat 3) Pathway in Multiple Myeloma
Quintanilla-Martinez, L., Kremer, M., Specht, K., Calzada-Wack, J., Nathrath, M., Schaich, R., Höfler, H., & Fend, F. (2003) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64278-2 · Cited by 93 · see citing works
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Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“…in chemotherapy resistance; there is a strong correlation between STAT3 activation and chemoresistance, and STAT3 inhibition has been shown to restore sensitivity of tumors to chemotherapeutic drugs (Real et al., 2002; Huang et al., 2012; Sims et al., 2013; Lee et al., 2014; Zhao et al., 2016).”
BackgroundTu, B., Zhu, J., Liu, S., Wang, L., Fan, Q., Hao, Y., Fan, C., & Tang, T.-T. (2016) · Oncotarget · doi:10.18632/oncotarget.10219 · Cited by 95 · see citing works
- Authors
- Huang, S., Chen, M., Shen, Y., Shen, W., Guo, H., Gao, Q., & Zou, X.
- Affiliations
- Nanjing Drum Tower Hospital (CN)
- Nanjing University (CN)
- Corresponding author
- Gao, Qian
- Zou, Xiaoping
- Venue
- Cancer Letters
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 315
- Issue
- 2
- Pages
- 198-205
- ISSN
- 0304-3835 (ISSN-L)
- OpenAlex
- W2115538785
- Cited by
- 94
- References
- 2
- Citations by year
- 2025: 3 · 2024: 3 · 2023: 4 · 2022: 1 · 2021: 6 · 2020: 3 · 2019: 3 · 2018: 12 · 2017: 12 · 2016: 9 · 2015: 11 · 2014: 15 · 2013: 10 · 2012: 2
- FWCI
- 4.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
- Keywords
- STAT3, gastric cancer, multidrug resistance, cisplatin resistance, STAT3 inhibitor, DPP, apoptosis, Bcl-2, c-Myc, p53, vacuolar ATPase, proton pump, drug uptake, chemotherapy resistance reversal
- MeSH terms
- Adenocarcinoma, Antineoplastic Agents, Cisplatin, Fluorescent Antibody Technique, Gene Expression Regulation, Humans, Stomach Neoplasms, Blotting, Western, Polymerase Chain Reaction, Drug Delivery Systems, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Cell Line, Tumor, Cell Proliferation, STAT3 Transcription Factor
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