Lactate Decreases Bortezomib Sensitivity and Predicts Poor Clinical Outcomes of Multiple Myeloma

Abstract

Objective

Metabolic disorders are regarded as hallmarks of multiple myeloma (MM) and are responsible for rapid cancer cell proliferation and tumor growth. However, the exact biological roles of metabolites in MM cells have not been fully explored. This study aimed to explore the feasibility and clinical significance of lactate for MM and investigate the molecular mechanism of lactic acid (Lac) in the proliferation of myeloma cells and cell sensitivity to bortezomib (BTZ).

Methods

Metabolomic analysis of the serum was carried out to obtain metabolites expression and clinical characteristics in MM patients. The CCK8 assay and flow cytometry were used to detect cell proliferation, apoptosis, and cell cycle changes. Western blotting was used to detect the potential mechanism and apoptosis- and cycle-related protein changes.

Results

Lactate was highly expressed in both the peripheral blood and bone marrow of MM patients. It was significantly correlated with Durie-Salmon Staging (DS Staging) and the International Staging System (ISS Staging) and the serum and urinary involved/uninvolved free light chain ratios. Patients with relatively high lactate levels had a poor treatment response. Moreover, in vitro experiments showed that Lac could promote the proliferation of tumor cells and decrease the proportion of G0/G1-phase cells, which was accompanied by an increased proportion of S-phase cells. In addition, Lac could decrease tumor sensitivity to BTZ by disrupting the expression of nuclear factor kappa B subunit 2 (NFkB2) and RelB.

Conclusion

Metabolic changes are important in MM cell proliferation and treatment response; lactate could be used as a biomarker in MM and as a therapeutic target to overcome cell resistance to BTZ.

Keywords

lactate / biomarker / multiple myeloma / bortezomib / NF-kappa B pathway

References

[1] RölligC, KnopS, BornhäuserM. Multiple myeloma. Lancet, 2015, 385(9983): 2197-2208

[2] CowanAJ, GreenDJ, KwokM, et al.. Diagnosis and Management of Multiple Myeloma. JAMA, 2022, 327(5): 464-477

[3] DurieBGM, SalmonSE. A clinical staging system for multiple myeloma correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer, 1975, 36(3): 842-854

[4] GreippPR, MiguelJS, DurieBGM, et al.. International Staging System for Multiple Myeloma. J Clin Oncol, 2005, 23(15): 3412-3420

[5] WarburgO, WindF, NegeleinE. The metabolism of tumors in the body. J Gen Physiol, 1927, 8(6): 519-530

[6] Moreno-FeliciJ, HyroššováP, AragóM, et al.. Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca²⁺. Cells, 2020, 9(1): 18

[7] RoudierE, BacheletC, PerrinA. Pyruvate reduces DNA damage during hypoxia and after reoxygenation in hepatocellular carcinoma cells. FEBS J, 2007, 274(19): 5188-5198

[8] HirschhaeuserF, SattlerUGA, Mueller-KlieserW. Lactate: A Metabolic Key Player in Cancer. Cancer Res, 2011, 71(22): 6921-6925

[9] NgwaVM, EdwardsDN, PhilipM, et al.. Microenvironmental Metabolism Regulates Antitumor Immunity. Cancer Res, 2019, 79(16): 4003-4008

[10] DongQ, ZhouC, RenH, et al.. Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells. Cell Commun Signal, 2020, 18(1): 167

[11] GovoniM, RossiV, Di StefanoG, et al.. Lactate Upregulates the Expression of DNA Repair Genes, Causing Intrinsic Resistance of Cancer Cells to Cisplatin. Pathol Oncol Res, 2021, 27: 1609951

[12] QuJ, SunZ, PengC, et al.. C. tropicalis promotes chemotherapy resistance in colon cancer through increasing lactate production to regulate the mismatch repair system. Int J Biol Sci, 2021, 17(11): 2756-2769

[13] RossiV, GovoniM, FarabegoliF, et al.. Lactate is a potential promoter of tamoxifen resistance in MCF7 cells. Biochim Biophys Acta Gen Subj, 2022, 1866(9): 130185

[14] UstunC, FallP, SzerlipHM, et al.. Multiple Myeloma Associated with Lactic Acidosis. Leuk Lymphoma, 2009, 43(12): 2395-2397

[15] AbdullahSY, AliMK, SabhaMM. Type-B lactic acidosis associated with progressive multiple myeloma. Saudi Med J, 2015, 36(2): 239-242

[16] RajkumarSV, DimopoulosMA, PalumboA, et al.. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol, 2014, 15(12): e538-e548

[17] GarcésJ, CedenaM, PuigN, et al.. Circulating Tumor Cells for the Staging of Patients With Newly Diagnosed Transplant-Eligible Multiple Myeloma. J Clin Oncol, 2022, 40(27): 3151-3161

[18] BertaminiL, OlivaS, Rota-ScalabriniD, et al.. High Levels of Circulating Tumor Plasma Cells as a Key Hallmark of Aggressive Disease in Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma. J Clin Oncol, 2022, 40(27): 3120-3131

[19] OkorieON, DellingerP. Lactate: Biomarker and Potential Therapeutic Target. Crit Care Clin, 2011, 27(2): 299-326

[20] HayesC, DonohoeCL, DavernM, et al.. The oncogenic and clinical implications of lactate induced immunosuppression in the tumour microenvironment. Cancer Lett, 2021, 500: 75-86

[21] MariappanR, VenkatraghavanL, VertanianA, et al.. Serum lactate as a potential biomarker of malignancy in primary adult brain tumours. J Clin Neurosci, 2015, 22(1): 144-148

[22] BrancoM, LinharesP, CarvalhoB, et al.. Serum lactate levels are associated with glioma malignancy grade. Clin Neurol Neurosurg, 2019, 186: 105546

[23] KumarSK, DispenzieriA, LacyMQ, et al.. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia, 2014, 28(5): 1122-1128

[24] JosephNS, KaufmanJL, DhodapkarMV, et al.. Long-Term Follow-Up Results of Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy and Risk-Adapted Maintenance Approach in Newly Diagnosed Multiple Myeloma. J Clin Oncol, 2020, 38(17): 1928-1937

[25] FrankeNE, NiewerthD, AssarafYG, et al.. Impaired bortezomib binding to mutant β5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells. Leukemia, 2012, 26(4): 757-768

[26] Dytfeld D, Luczak M, Wrobel T, et al. Comparative proteomic profiling of refractory/relapsed multiple myeloma reveals biomarkers involved in resistance to bortezomib-based therapy. Oncotarget, 2016–7(35):56726–56736

[27] QiangY, YeS, ChenY, et al.. MAF protein mediates innate resistance to proteasome inhibition therapy in multiple myeloma. Blood, 2016, 128(25): 2919-2930

[28] ZhangL, RastgooN, WuJ, et al.. MARCKS inhibition cooperates with autophagy antagonists to potentiate the effect of standard therapy against drug-resistant multiple myeloma. Cancer Lett, 2020, 480: 29-38

[29] AnnunziataCM, DavisRE, DemchenkoY, et al.. Frequent Engagement of the Classical and Alternative NF-κB Pathways by Diverse Genetic Abnormalities in Multiple Myeloma. Cancer Cell, 2007, 12(2): 115-130

[30] KeatsJJ, FonsecaR, ChesiM, et al.. Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple Myeloma. Cancer Cell, 2007, 12(2): 131-144