期刊
HELIYON
卷 7, 期 1, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.heliyon.2020.e05849
关键词
Hematologic neoplasms; Progranulin; Mechanistic target of rapamycin complex 1; Transforming growth factor beta
资金
- AT corporation
- JSPS KAKENHI [18K19761, 19K07490, 17H04252]
- Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)
- Smoking Research Foundation
- Grants-in-Aid for Scientific Research [18K19761, 17H04252, 19K07490] Funding Source: KAKEN
Progranulin plays a crucial role in hematopoietic cancers, modulating cell proliferation via the TGF-β axis. Studies suggest that Progranulin could be a potential new therapeutic target for hematopoietic cancers.
Progranulin is an autocrine growth factor that promotes proliferation, migration, invasion, and chemoresistance of various cancer cells. These mechanisms mainly depend on the protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway. Recent studies have shown that patients with hematopoietic cancer have elevated serum progranulin levels. Thus, the current study aimed to investigate the role of progranulin in hematopoietic cancer cells and how it modulates their proliferation. Both knockdown of progranulin and progranulin neutralizing antibody treatment inhibited proliferation in several human hematopoietic cancer cell lines. Moreover, progranulin depletion not only decreases the phosphorylation level of the Akt/mTOR pathway but also, surprisingly, increases the expression of transforming growth factor-beta (TGF-beta) and phosphorylation of mothers against decapentaplegic homolog 2 (SMAD2) in Kasumi-1 cell. Furthermore, LY2109761, an inhibitor of TGF-beta receptor type I/II kinase, and TGF-beta neutralizing antibody blocked the inhibition of proliferation induced by progranulin depletion. These data provide new insights that progranulin alters cell proliferation via the TGF-beta axis and progranulin could be a new therapeutic target for hematopoietic cancers.
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