Polysaccharide K induces Mn superoxide dismutase (Mn-SOD) in tumor tissues and inhibits malignant progression of QR-32 tumor cells: possible roles of interferon alpha, tumor necrosis factor alpha and transforming growth factor beta in Mn-SOD induction by polysaccharide K.
Previously we reported the malignant progression of QR-32, a regressor-type tumor clone, following co-implantation with foreign bodies (gelatin sponge or plastic plate) in normal syngeneic C57BL/6 mice. We also reported that the progression of QR-32 cells by a gelatin sponge was significantly inhibited in the mice administered polysaccharide K (PSK) and that PSK induced an increase of radical scavengers, especially manganese superoxide dismutase (Mn-SOD), locally at the site of tumor tissues. In this study, to reveal the possible mechanism by which PSK induced Mn-SOD in the tumor tissues, we examined the mRNA expression and protein levels of inflammatory cytokines in the tissues. We found that mRNAs of tumor necrosis factor alpha (TNFalpha) and interleukin-1alpha (IL-1alpha) were considerably expressed in both PSK-treated and phosphate-buffered-saline-treated tumors, and that the mRNA expression and protein level of interferon gamma (IFNgamma) increased in the tumor tissues treated with PSK. In vitro treatment of QR-32 cells with IFNgamma did not significantly increase the production of Mn-SOD; however, the combination of IFNgamma with TNFalpha increased the Mn-SOD production more effectively than did any of the cytokines used singly. Furthermore, we observed the down-regulation of the mRNA expression and protein level of transforming growth factor beta (TGFbeta) in the tumor tissues treated with PSK, and that in vitro treatment of QR-32 cells with TGFbeta decreased the production of Mn-SOD. These results suggest that PSK suppresses the progression of QR-32 cells by increasing Mn-SOD via the modulation of inflammatory cytokines; that is, by decreasing TGF-beta and increasing IFN-gamma.
Laboratory of Pathology, Cancer Institute, Hokkaido University School of Medicine, Sapporo, Japan.
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H
Habelhah
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Okada
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Nakai
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SK
Choi
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Hamada
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Kobayashi
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Hosokawa
D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control / Q000556:secondary / Q000628:therapy*; D005549:Foreign-Body Reaction / Q000473:pathology; D005780:Gelatin; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016898:Interferon-alpha / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D007375:Interleukin-1 / Q000502:physiology; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008345:Manganese / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009368:Neoplasm Transplantation; D011509:Proteoglycans / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D015503:Surgical Sponges; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
D000276:Adjuvants, Immunologic; D016898:Interferon-alpha; D007375:Interleukin-1; D009363:Neoplasm Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C010770:polysaccharide-K; D008345:Manganese; D007371:Interferon-gamma; D005780:Gelatin; D013482:Superoxide Dismutase