Cyclophilin A is a factor of antitumor defense in the early stages of tumor development

• Published in: International immunopharmacology 2021-05, Vol.94, p.107470, Article 107470
• Main Authors: Kalinina, Anastasiia, Golubeva, Irina, Kudryavtsev, Igor, Khromova, Natalia, Antoshina, Elena, Trukhanova, Lubov, Gorkova, Tatyana, Kazansky, Dmitry, Khromykh, Ludmila
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Adenocarcinoma; Angiogenesis; Animals; Anticancer properties; Antimetastatic effect; Antineoplastic Agents - therapeutic use; Antitumor activity; Antitumor effect; Cancer; CD147 antigen; Cell Line, Tumor; Cell Proliferation - drug effects; Cervical cancer; Cervix; Cyclophilin A - genetics; Cyclophilin A - pharmacology; Cyclophilin A - therapeutic use; Cytotoxicity; Female; Fluorouracil - therapeutic use; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immune modulator; Inflammation; Injection; Leukemia; Leukopenia; Lung carcinoma; Malignancy; Matrix metalloproteinase; Matrix Metalloproteinases - genetics; Melanoma; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Recombinant human cyclophilin A; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; Tumor cells; Tumor microenvironment; Tumors
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2021.107470

[Display omitted] •CypA exhibits antitumor effect on initial stages of tumor formation.•CypA enhances 5FU antitumor effect in the combined therapy of cervical cancer model.•CypA suppresses the earliest stages of post-surgery LLC metastases formation.•CypA stimulates production of tumor-protective MMPs in primary B16 melanoma tissues. Cyclophilin A (CypA) is a pro-inflammatory factor with multiple immunomodulating effects. Here, we investigated the effects of recombinant human CypA (rhCypA) as a factor of antitumor host defense. Our results demonstrated that rhCypA dramatically inhibited the growth of murine transplantable tumors (mammary adenocarcinoma Ca755, melanoma B16, Lewis lung carcinoma (LLC), and cervical cancer CC-5). In the B16 model, rhCypA effects were observed only when tumor cells were transplanted at the significantly reduced injection dose, indicating that antitumor properties of rhCypA are more effective at the initial stages of cancer development. Antitumor effect of rhCypA in the CC-5 model was comparable to the action of 5-fluorouracil (5FU), and rhCypA administration prevented 5FU - induced leukopenia in the blood of tumor-bearing mice. In the LLC model, rhCypA injection before but not after tumor resection significantly suppressed the formation of post-surgical metastases. RhCypA exhibited no direct cytotoxic effects in vitro on human leukemia cells (K-562, HL-60, KG-1), indicating that rhCypA antitumor action could be mediated by its immunomodulating activity. In the B16 model, rhCypA had no impact on tumor angiogenesis and gene expression of several MMPs, endogenous CypA, and CD147, which play a crucial role in cancer progression. However, in this model, rhCypA stimulated gene expression of MMPs 8, 9, and 12 that could contribute to malignancy growth inhibition. Here, our findings pointed out CypA as one of the factors of antitumor host defense that can effectively control the initial stages of tumor and metastases formation by regulating the action of MMPs and changing the tumor microenvironment.