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Cited by 160Pancreatic and Hepatic Oncology ResearchTGF-β signaling in diseasesAutophagy in Disease and Therapy

The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.

SMAD4 Gene Mutation Renders Pancreatic Cancer Resistance to Radiotherapy through Promotion of Autophagy

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Wang, Feng, Xia, Xiaojun, Yang, Chunying, Shen, Jianliang, Mai, Junhua, Kim, Han-Cheon, Kirui, Dickson, Kang, Ya'an, Fleming, Jason B., Koay, Eugene J., Mitra, Sankar, Ferrari, Mauro, Shen, Haifa·2018·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-17-3435PMC PMC6345154

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Abstract

Purpose: Understanding the mechanism of radioresistance could help develop strategies to improve therapeutic response of patients with PDAC. The SMAD4 gene is frequently mutated in pancreatic cancer. In this study, we investigated the role of SMAD4 deficiency in pancreatic cancer cells' response to radiotherapy. Experimental Design: We downregulated SMAD4 expression with SMAD4 siRNA or SMAD4 shRNA and overexpressed SMAD4 in SMAD4 mutant pancreatic cancer cells followed by clonogenic survival assay to evaluate their effects on cell radioresistance. To study the mechanism of radioresistance, the effects of SMAD4 loss on reactive oxygen species (ROS) and autophagy were determined by flow cytometry and immunoblot analysis, respectively. Furthermore, we measured radioresistance by clonogenic survival assay after treatment with autophagy inhibitor (Chloroquine) and ROS inhibitor (N-acetyl-l-cysteine) in SMAD4-depleted pancreatic cancer cells. Finally, the effects of SMAD4 on radioresistance were also confirmed in an orthotopic tumor model derived from SMAD4-depleted Panc-1 cells. Results: SMAD4-depleted pancreatic cancer cells were more resistant to radiotherapy based on clonogenic survival assay. Overexpression of wild-type SMAD4 in SMAD4-mutant cells rescued their radiosensitivity. Radioresistance mediated by SMAD4 depletion was associated with persistently higher levels of ROS and radiation-induced autophagy. Finally, SMAD4 depletion induced in vivo radioresistance in Panc-1-derived orthotopic tumor model (P = 0.038). More interestingly, we observed that the protein level of SMAD4 is inversely correlated with autophagy in orthotopic tumor tissue samples. Conclusions: Our results demonstrate that defective SMAD4 is responsible for radioresistance in pancreatic cancer through induction of ROS and increased level of radiation-induced autophagy. Clin Cancer Res; 24(13); 3176–85. ©2018 AACR.

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  • SMAD4 loss is associated with poor prognosis and shorter survival, but its impact on chemotherapy response may vary based on treatment regimens and disease stages.

    “While SMAD4 loss is associated with poor prognosis and shorter survival, its impact on chemotherapy response may vary, based on specific treatment regimens and disease stages [64,70,71].”

    From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [64]

    The Introduction (page not provided) reports that SMAD4 loss is associated with pancreatic cancer progression and poorer overall survival. It mentions chemotherapy resistance in other cancers, but does not say that the effect of SMAD4 loss on chemotherapy response varies by treatment regimen or disease stage. This paper chiefly investigates radiotherapy response. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • SMAD4 loss alone may not initiate tumor formation but can promote tumor progression initiated by other genes, such as KRAS activation in PDAC and APC inactivation in colorectal cancer.

    “For instance, SMAD4 loss alone may not initiate tumor formation but can promote tumor progression initiated by other genes, such as KRAS activation in pancreatic ductal adenocarcinoma and APC inactivation in colorectal cancer.”

    From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [64]

    The Introduction (page unavailable) says SMAD4 loss promotes pancreatic tumor progression and identifies KRAS among genes important to PDAC progression. Reference 21 describes cooperation between Kras activation and Smad4 loss in pancreatic neoplasms. Our copy does not say that SMAD4 loss alone cannot initiate tumors or that it promotes colorectal cancer progression following APC inactivation. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • In PDAC, SMAD4 mutations promote tumor progression and metastasis, induce resistance to radiotherapy and correlate with poor prognosis.

    “As aforementioned, in PDAC, SMAD4 mutations have profound implications, promoting tumor progression and metastasis, inducing resistance to radiotherapy and correlating with poor prognosis.”

    From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [64]

  • Knocking down SMAD4 in pancreatic cancer cells leads to increased radio-resistance, heightened DNA damage, genomic instability and decreased levels of key DNA double-strand break repair proteins.

    “Knocking down SMAD4 in pancreatic cancer cells leads to increased radio-resistance, heightened DNA damage, genomic instability and decreased levels of key DNA double-strand break repair proteins [64,117].”

    From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [64]

  • SMAD4 depletion induces resistance to ionizing radiation.

    “Additionally, a study exploring SMAD4 gene mutation’s impact on pancreatic cancer response to radiotherapy reveals that SMAD4 depletion induces resistance to ionizing radiation.”

    From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [64]

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Metadata

Authors
Wang, F., Xia, X., Yang, C., Shen, J., Mai, J., Kim, H.-C., Kirui, D., Kang, Y., Fleming, J. B., Koay, E. J., Mitra, S., Ferrari, M., & Shen, H.
Affiliations
  • Tongji University (CN)
  • Houston Methodist (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • 1Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas.
Corresponding author
Shen, Haifa
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2018-07-01
Volume
24
Issue
13
Pages
3176-3185
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-17-3435
PMC
PMC6345154
OpenAlex
W2794847062
Cited by
160
References
6
Citations by year
2026: 6 · 2025: 14 · 2024: 30 · 2023: 28 · 2022: 24 · 2021: 30 · 2020: 20 · 2019: 8
FWCI
5.45
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
Department of Defense (1R01CA193880, U54CA143837, and U54CA210181)
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords
SMAD4, pancreatic ductal adenocarcinoma, radioresistance (biology), autophagy, reactive oxygen species, SMAD4 mutation, radiosensitivity, chloroquine, N-acetylcysteine, orthotopic tumor model, PANC-1 cells
MeSH terms
Animals, Antineoplastic Agents, Autophagy, Cell Survival, Disease Models, Animal, DNA Damage, Humans, Immunohistochemistry, Mutation, Pancreatic Neoplasms, Radiation Tolerance, Biomarkers, Tumor, Apoptosis, Reactive Oxygen Species, Genomic Instability, Cell Line, Tumor, Cell Proliferation, Mice, Smad4 Protein, Gene Knockdown Techniques

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