Open Access

ARTICLE

Identification of TNFRSF1A as a novel regulator of carfilzomib resistance in multiple myeloma

by JIE ZHAO^1,#, XUANTAO YANG^2,#, HAIXI ZHANG¹, XUEZHONG GU^1,*

1 Department of Hematology, The First People’s Hospital of Yunnan Province, Yunnan Province Clinical Research Center for Hematologic Disease, Yunnan Province Clinical Center for Hematologic Disease, Kunming, 650032, China
2 Department of Pathology, The First People’s Hospital of Yunnan Province, Kunming, 650032, China

* Corresponding Author: XUEZHONG GU. Email:
# These authors contributed equally

Oncology Research 2024, 32(2), 325-337. https://doi.org/10.32604/or.2023.030770

Received 21 April 2023; Accepted 20 July 2023; Issue published 28 December 2023

Abstract

Multiple myeloma (MM) is a hematological tumor with high mortality and recurrence rate. Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM. However, the development of drug resistance is a pervasive obstacle to treating MM. Therefore, elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies. To elucidate the mechanisms of carfilzomib resistance, we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells. Differential gene expression analyses revealed major alterations in the major histocompatibility complex (MHC) and cell adhesion molecules. The upregulation of the tumor necrosis factor (TNF) receptor superfamily member 1A (TNFRSF1A) gene was accompanied by the downregulation of MHC genes and cell adhesion molecules. Furthermore, to investigate the roles of these genes, we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules. Furthermore, TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice, indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity. Furthermore, our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules. The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity. Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.

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Supplementary Material

Supplementary Material File

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