TY - JOUR
T1 - Therapeutic advantage of genetically engineered Salmonella typhimurium carrying short hairpin RNA against inhibin alpha subunit in cancer treatment
AU - Yoon, W.
AU - Yoo, Y.
AU - Chae, Y. S.
AU - Kee, S. H.
AU - Kim, B. M.
N1 - Funding Information:
This study was also supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare Affairs, Republic of Korea (No. HI08C2149), by a faculty research grant from Yonsei University College of Medicine for 2016 (No. 2016-32-0061) and 2017 (No. 2017-32-0099), and by Basic Science Research Program through the NRF funded by the Ministry of Education (No. 2016R1D1A1B03930899) to BMK.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/9/1
Y1 - 2018/9/1
N2 - Background In contrast to its well-known endocrine function, the role of inhibin in cancer development and therapeutic response is unclear. Salmonella, particularly less toxic attenuated Salmonella strains, are used to treat cancer in two ways. First, Salmonella accumulate around tumors, penetrate the cell barrier, and replicate inside the tumors. Second, Salmonella can act as a vehicle for delivering anticancer agents or proapoptotic genes to attack tumors. In this study, we aimed to develop a suitable cancer therapeutic strategy by genetically modifying attenuated Salmonella typhimurium to harbor short hairpin RNA (shRNA) expression plasmids targeting alpha subunit of inhibin (sh-INHA). Methods We analyzed the expression of human INHA in normal and cancer cells and tissues. We developed genetically engineered attenuated S. typhimurium harboring sh-INHA (S. typhimurium/sh-INHA) and assessed its cancer therapeutic effects by using cell culture models and syngeneic mouse tumor models. Results INHA expression levels were markedly higher in colon cancer and melanoma cells and tissues than in their normal counterparts. Suppression of INHA expression mildly reduced cancer cell survival and induced caspase activation and downregulation of anti-apoptotic Bcl-2 and Bcl-xL expressions. Although the genetically engineered S. typhimurium mildly interfered with the invasion of S. typhimurium into host colon cancer and melanoma cells, S. typhimurium/sh-INHA caused remarkable cytotoxicity in cancer compared with unmodified S. typhimurium or S. typhimurium expressing a control scrambled shRNA (S. typhimurium/sh-Cont). Salmonella typhimurium/sh-INHA-treated mice also showed a significantly inhibited growth of colon cancers and melanomas, with a survival advantage. Conclusion Our results suggest that tumor-targeted therapy using S. typhimurium/sh-INHA may provide a novel cancer treatment option.
AB - Background In contrast to its well-known endocrine function, the role of inhibin in cancer development and therapeutic response is unclear. Salmonella, particularly less toxic attenuated Salmonella strains, are used to treat cancer in two ways. First, Salmonella accumulate around tumors, penetrate the cell barrier, and replicate inside the tumors. Second, Salmonella can act as a vehicle for delivering anticancer agents or proapoptotic genes to attack tumors. In this study, we aimed to develop a suitable cancer therapeutic strategy by genetically modifying attenuated Salmonella typhimurium to harbor short hairpin RNA (shRNA) expression plasmids targeting alpha subunit of inhibin (sh-INHA). Methods We analyzed the expression of human INHA in normal and cancer cells and tissues. We developed genetically engineered attenuated S. typhimurium harboring sh-INHA (S. typhimurium/sh-INHA) and assessed its cancer therapeutic effects by using cell culture models and syngeneic mouse tumor models. Results INHA expression levels were markedly higher in colon cancer and melanoma cells and tissues than in their normal counterparts. Suppression of INHA expression mildly reduced cancer cell survival and induced caspase activation and downregulation of anti-apoptotic Bcl-2 and Bcl-xL expressions. Although the genetically engineered S. typhimurium mildly interfered with the invasion of S. typhimurium into host colon cancer and melanoma cells, S. typhimurium/sh-INHA caused remarkable cytotoxicity in cancer compared with unmodified S. typhimurium or S. typhimurium expressing a control scrambled shRNA (S. typhimurium/sh-Cont). Salmonella typhimurium/sh-INHA-treated mice also showed a significantly inhibited growth of colon cancers and melanomas, with a survival advantage. Conclusion Our results suggest that tumor-targeted therapy using S. typhimurium/sh-INHA may provide a novel cancer treatment option.
KW - RNA interference (RNAi)
KW - genetically modified attenuated Salmonella typhimurium
KW - inhibin alpha subunit (INHA)
KW - syngeneic mouse models utilizing immunocompetent mice bearing tumors
KW - treatment option for cancer therapy
UR - http://www.scopus.com/inward/record.url?scp=85054291170&partnerID=8YFLogxK
U2 - 10.1093/annonc/mdy240
DO - 10.1093/annonc/mdy240
M3 - Article
C2 - 30016386
AN - SCOPUS:85054291170
SN - 0923-7534
VL - 29
SP - 2010
EP - 2017
JO - Annals of Oncology
JF - Annals of Oncology
IS - 9
ER -
