Progranulin depletion inhibits proliferation via the transforming growth factor beta/SMAD family member 2 signaling axis in Kasumi-1 cells

Kuniaki Yabe,Yasuko Yamamoto,Masao Takemura,Takeshi Hara,Hisashi Tsurumi,Ginette Serrero,Toshitaka Nabeshima,Kuniaki Saito

doi:10.1016/j.heliyon.2020.e05849

Abstract

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-β) and phosphorylation of mothers against decapentaplegic homolog 2 (SMAD2) in Kasumi-1 cell. Furthermore, LY2109761, an inhibitor of TGF-β receptor type I/II kinase, and TGF-β neutralizing antibody blocked the inhibition of proliferation induced by progranulin depletion. These data provide new insights that progranulin alters cell proliferation via the TGF-β axis and progranulin could be a new therapeutic target for hematopoietic cancers.

Highlights

Hematopoietic malignancies are types of cancer arising from hematopoietic cells, which are found in the blood, bone marrow, lymph nodes, and spleen
Because over 80% of newly diagnosed patients with hematopoietic malignancies suffer from lymphoma and leukemia [29], cell lines such as Daudi (Burkitt lymphoma), HL60, Kasumi-1, RAJI (Burkitt lymphoma), and SLVL were used to investigate the role of progranulin in the proliferation of human hematopoietic cancer cells
We investigated whether extracellular progranulin level was decreased in Kasumi-1 cells transfected progranulin-specific siRNA, since progranulin is an autocrine growth factor found in extracellular fluids, including serum

Summary

Introduction

Hematopoietic malignancies are types of cancer arising from hematopoietic cells, which are found in the blood, bone marrow, lymph nodes, and spleen. Progranulin, known as GP88, granulin–epithelin precursor, acrogranin, or PC-cell derived growth factor, is a multifunctional growth factor containing 7.5 repeats of a double cysteine-rich motif [1] It is involved in the proliferation, migration, and invasion of cancer cells and chemoresistance in breast, bladder, colorectal, ovarian, cervical, and hepatocellular cancer and malignant melanoma [2, 3, 4, 5, 6, 7, 8, 9]. Lung, prostate, and ovarian cancer, glioblastoma, chronic lymphocytic leukemia, and malignant lymphoma have elevated serum progranulin level, which is associated with decreased overall survival, disease-free survival, relapse-free survival, and progression-free survival [10, 11, 12, 13, 14, 15,16, 17]. Progranulin could be a useful independent prognostic marker for these hematologic malignancies

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