title: Ratio of phosphorylated HSP27 to nonphosphorylated HSP27 biphasically acts as a determinant of cellular fate in gemcitabine-resistant pancreatic cancer cells.
abstract: Gemcitabine has been used most commonly as an anticancer drug to treat advanced pancreatic cancer patients. However, intrinsic or acquired resistance of pancreatic cancer to gemcitabine was also developed, which leads to very low five-year survival rates. Here, we investigated whether cellular levels of HSP27 phosphorylation act as a determinant of cellular fate with gemcitabine. In addition we have demonstrated whether HSP27 downregulation effectively could overcome the acquisition of gemcitabine resistance by using transcriptomic analysis. We observed that gemcitabine induced p38/HSP27 phosphorylation and caused acquired resistance. After acquisition of gemcitabine resistance, cancer cells showed higher activity of NF-κB. NF-κB activity, as well as colony formation in gemcitabine-resistant pancreatic cancer cells, was significantly decreased by HSP27 downregulation and subsequent TRAIL treatment, showing that HSP27 was a common network mediator of gemcitabine/TRAIL-induced cell death. After transcriptomic analysis, gene fluctuation after HSP27 downregulation was very similar to that of pancreatic cancer cells susceptible to gemcitabine, and then in opposite position to that of acquired gemcitabine resistance, which makes it possible to downregulate HSP27 to overcome the acquired gemcitabine resistance to function as an overall survival network inhibitor. Most importantly, we demonstrated that the ratio of phosphorylated HSP27 to nonphosphorylated HSP27 rather than the cellular level of HSP27 itself acts biphasically as a determinant of cellular fate in gemcitabine-resistant pancreatic cancer cells.
authors.affiliation: Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Oncology, Affiliated Hospital of Yanbian University, Yanji, Jilin Province, PR China.
authors.forename: Dongxu
authors.initials: D
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sujin
authors.initials: S
authors.lastname: Kang
authors.affiliation: Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Bioscience and Biotechnology, Konkuk University, Seoul, Republic of Korea.
authors.forename: Yong-Sic
authors.initials: YS
authors.lastname: Hwang
authors.affiliation: Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Suyeon
authors.initials: S
authors.lastname: Je
authors.affiliation: Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Oncology, Affiliated Hospital of Yanbian University, Yanji, Jilin Province, PR China.
authors.forename: Zhezhu
authors.initials: Z
authors.lastname: Han
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: kjhang@yuhs.ac.
authors.forename: Joo-Hang
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: jjs109@yuhs.ac.
authors.forename: Jae J
authors.initials: JJ
authors.lastname: Song
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D055551:HSP27 Heat-Shock Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D055551:HSP27 Heat-Shock Proteins; D016328:NF-kappa B; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Gemcitabine; Nonphosphorylated HSP27; Pancreatic cancer; Phosphorylated HSP27