PMID- 33490663 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210714 IS - 2405-8440 (Print) IS - 2405-8440 (Electronic) IS - 2405-8440 (Linking) VI - 7 IP - 1 DP - 2021 Jan TI - Progranulin depletion inhibits proliferation via the transforming growth factor beta/SMAD family member 2 signaling axis in Kasumi-1 cells. PG - e05849 LID - 10.1016/j.heliyon.2020.e05849 [doi] LID - e05849 AB - 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. CI - (c) 2020 The Author(s). FAU - Yabe, Kuniaki AU - Yabe K AD - Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Aichi, Japan. AD - A&T corporation, Kanagawa, Japan. FAU - Yamamoto, Yasuko AU - Yamamoto Y AD - Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Aichi, Japan. FAU - Takemura, Masao AU - Takemura M AD - Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Sciences, Aichi, Japan. FAU - Hara, Takeshi AU - Hara T AD - Department of Hematology, Matsunami General Hospital, Gifu, Japan. FAU - Tsurumi, Hisashi AU - Tsurumi H AD - Department of Hematology, Matsunami General Hospital, Gifu, Japan. FAU - Serrero, Ginette AU - Serrero G AD - University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA. AD - A&G Pharmaceutical, Inc., Columbia, MD, USA. FAU - Nabeshima, Toshitaka AU - Nabeshima T AD - Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Sciences, Aichi, Japan. AD - Japanese Drug Organization of Appropriate Use and Research, Nagoya, 468-0069, Japan. FAU - Saito, Kuniaki AU - Saito K AD - Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Aichi, Japan. AD - Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Sciences, Aichi, Japan. AD - Japanese Drug Organization of Appropriate Use and Research, Nagoya, 468-0069, Japan. AD - Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan. LA - eng GR - R44 CA162629/CA/NCI NIH HHS/United States GR - R44 CA224718/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20210108 PL - England TA - Heliyon JT - Heliyon JID - 101672560 PMC - PMC7809376 OTO - NOTNLM OT - Hematologic neoplasms OT - Mechanistic target of rapamycin complex 1 OT - Progranulin OT - Transforming growth factor beta COIS- The authors declare the following conflict of interests: Kuniaki Yabe; performed this study while an employee of A&T corporation. Ginette Serrero; performed this study while an employee of A&G Pharmaceutical and is also a shareholder of A&G Pharmaceutical. The remaining authors declare no conflict of interest. EDAT- 2021/01/26 06:00 MHDA- 2021/01/26 06:01 PMCR- 2021/01/08 CRDT- 2021/01/25 05:46 PHST- 2020/08/30 00:00 [received] PHST- 2020/11/27 00:00 [revised] PHST- 2020/12/22 00:00 [accepted] PHST- 2021/01/25 05:46 [entrez] PHST- 2021/01/26 06:00 [pubmed] PHST- 2021/01/26 06:01 [medline] PHST- 2021/01/08 00:00 [pmc-release] AID - S2405-8440(20)32691-8 [pii] AID - e05849 [pii] AID - 10.1016/j.heliyon.2020.e05849 [doi] PST - epublish SO - Heliyon. 2021 Jan 8;7(1):e05849. doi: 10.1016/j.heliyon.2020.e05849. eCollection 2021 Jan.