title: Differential effects of peptidoglycan on colorectal tumors and intestinal tissue post-pelvic radiotherapy.
abstract: Immediate medical intervention is required after pelvic tumor radiotherapy to protect the radiosensitive intestine and also to mitigate tumor growth. Toll-like receptors (TLRs) have been shown to promote tissue repair processes. Here, we analyzed the effect observed upon combining the TLR2 agonist, peptidoglycan (PGN), with radiation therapy on tumors as well as intestinal tissue, both in vitro and in vivo. In contrast to radiotherapy alone, PGN when combined with ionizing radiation (IR) elicited enhanced antitumor effects and also reduced the IR-induced intestinal damage. Mechanistic studies showed that PGN first induced an IL13 response in the irradiated intestine, but was decreased in tumor cell models screened by Th1/Th2 FlowCytomix assay and validated by the application of IL13 and anti-IL13 neutralizing antibodies. Next, PGN stimulated Akt3, but not Akt1/2, as was verified by AKT1/2/3 plasmid transfection assay and in AKT1/2/3 knockout mice in vivo. Akt3 expression was inhibited in 20 μg/mL PGN-treated tumor cells and in 1.5 mg/kg PGN-treated mouse tumor models. However, Akt3 was raised via IL13 in the irradiated intestine and human intestinal cell line after the same treatment. Finally, PGN activated mTOR via IL13/AKT3 in the intestine and restored intestinal structure and function. As an adjuvant to radiotherapy, PGN inhibited tumorigenesis by suppression of mTOR activity. To summarize, the IL13/AKT3/mTOR pathway was lessened in PGN-treated irradiated tumors but was raised in the normal intestine tissue. This distinct effect of PGN on normal and tumor tissues during pelvic radiotherapy suggests that PGN may be a promising adjuvant therapy to radiation.
authors.affiliation: School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, P.R. China.
authors.forename: Gen
authors.initials: G
authors.lastname: Li
authors.affiliation: School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, P.R. China.
authors.forename: Anqing
authors.initials: A
authors.lastname: Wu
authors.affiliation: School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, P.R. China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Qi
authors.affiliation: School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, P.R. China.|Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, P.R. China.
authors.forename: Fengmei
authors.initials: F
authors.lastname: Cui
authors.affiliation: School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, P.R. China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Pathology, School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.affiliation: Stem Cell Research Laboratory of Jiangsu Province, Suzhou 215007, P.R. China.|Jiangsu Institute of Clinical Immunology, Suzhou 215007, P.R. China.
authors.forename: Hongya
authors.initials: H
authors.lastname: Wu
authors.affiliation: Experimental Centre of Medical College, Soochow University, Suzhou 215123, P.R. China.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Gu
authors.affiliation: School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, P.R. China.|Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, P.R. China.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Stem Cell Research Laboratory of Jiangsu Province, Suzhou 215007, P.R. China.|Jiangsu Institute of Clinical Immunology, Suzhou 215007, P.R. China.
authors.forename: Xueguang
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D003131:Combined Modality Therapy; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D010457:Peptidoglycan / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011878:Radiotherapy; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018793:Interleukin-13; D010457:Peptidoglycan; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt
keywords: IL13-AKT3-mTOR pathway; colorectal tumor; intestine; pelvic radiotherapy; peptidoglycan