title: Effect of Smad3/4 on chemotherapeutic drug sensitivity in colorectal cancer cells.
abstract: Smad3 and Smad4 are signaling mediators in the transforming growth factor β (TGFβ) pathway and play a major role in the progression and migration of many types of cancers. The TGFβ pathway is correlated with resistance against both targeted and conventional chemotherapeutic drugs. The aim of this study was to determine the effect of Smad3/4 on drug sensitivity in chemotherapy-resistant colorectal cancer (CRC) cells. We isolated the TGFβ-mediated chemoresistant CRC cell line DLD1-5FU-C10, which showed high expression of Smad3/4 and p21. In order to analyze the influence of Smad3/4 on drug sensitivity in DLD1-5FU-C10 cells, we knocked down Smad3/4 using small interfering RNAs (siRNA). The results showed similar drug sensitivity between the DLD1‑5FU-C10 and the DLD1 control cells and reduced p21 expression. In addition, we found a significant increase in the levels of 3 TGFβ downstream factors: interleukin 6 (IL6), plasminogen activator (PLAU) and prostaglandin-endoperoxide synthase 2 (PTGS2). Furthermore, we showed that Smad3/4 regulated the JAK1/STAT3 pathway via IL6 in the chemoresistant CRC cell line. In conclusion, we identified Smad3/4 as a novel drug sensitivity regulator in TGFβ-mediated chemotherapy-resistant CRC cells. Our results suggest that Smad3/4 regulate p-STAT3 signaling by IL6 and p21 and highlight an important role for STAT3 signaling in Smad3/4 regulated drug sensitivity in chemoresistant CRC cells.
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-do 463-070, Republic of Korea.
authors.forename: Sung Ung
authors.initials: SU
authors.lastname: Moon
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-do 463-070, Republic of Korea.
authors.forename: Mi Hyun
authors.initials: MH
authors.lastname: Kang
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-do 463-070, Republic of Korea.
authors.forename: Ji Hea
authors.initials: JH
authors.lastname: Sung
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-do 463-070, Republic of Korea.
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-do 463-070, Republic of Korea.
authors.forename: Jeong Ok
authors.initials: JO
authors.lastname: Lee
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-do 463-070, Republic of Korea.
authors.forename: Yu Jung
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-do 463-070, Republic of Korea.
authors.forename: Keun Wook
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-do 463-070, Republic of Korea.
authors.forename: Soo Mee
authors.initials: SM
authors.lastname: Bang
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-do 463-070, Republic of Korea.
authors.forename: Jong Seok
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, Gyeonggi-do 463-070, Republic of Korea.
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D000964:Antimetabolites, Antineoplastic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051900:Smad3 Protein; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D005472:Fluorouracil