A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration

Amachi, Ryota; Hiasa, Masahiro; Teramachi, Jumpei; Harada, Takeshi; Oda, Asuka; Nakamura, Shingen; Hanson, Derek; Watanabe, Keiichiro; Fujii, Shiro; Miki, Hirokazu; Kagawa, Keiichiro; Iwasa, Masami; Endo, Itsuro; Kondo, Takeshi; Yoshida, Sumiko; Aihara, Ken‐ichi; Kurahashi, Kiyoe; Kuroda, Yuko; Horikawa, Hideaki; Tanaka, Eiji; Matsumoto, Toshio; Abe, Masahiro

doi:10.18632/oncotarget.11927

Cited by 11 publications

(11 citation statements)

References 50 publications

(40 reference statements)

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“…MM cells and OCs mutually interact with each other to enhance MM tumour growth while developing osteoclastic bone lesions (Abe et al , , ; Yaccoby et al , , ; Ge et al , ). The MM‐OC interactions in bone lesions in MM appear to create a highly acidic milieu due to protons released by OCs and lactate by proliferating glycolytic MM cells (Nakano et al , , ; Amachi et al , ). Acidic microenvironments are generally accepted to confer drug resistance and immune evasion capability in cancers (Kato et al , ).…”

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confidence: 99%

Unique anti‐myeloma activity by thiazolidine‐2,4‐dione compounds with Pim inhibiting activity

et al. 2018

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Proviral Integrations of Moloney virus 2 (PIM2) is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX-6258 and PIM447. SMI-16a also suppressed the drug efflux function of breast cancer resistance protein, minimized the sizes of side populations and reduced in vitro colony-forming capacity and in vivo tumourigenic activity in MM cells, suggesting impairment of their clonogenic capacity. PIM2 is known to be subject to ubiquitination-independent proteasomal degradation. Consistent with this, the proteasome inhibitors bortezomib and carfilzomib increased PIM2 protein levels in MM cells without affecting its mRNA levels. However, SMI-16a mitigated the PIM2 protein increase and cooperatively enhanced anti-MM effects in combination with carfilzomib. Collectively, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a uniquely reduce PIM2 protein in MM cells, which may contribute to their profound efficacy in addition to their immediate kinase inhibition. Their combination with proteasome inhibitors is envisioned.

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confidence: 99%

Unique anti‐myeloma activity by thiazolidine‐2,4‐dione compounds with Pim inhibiting activity

et al. 2018

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“…Lactic acid, the metabolic end product of anaerobic glycolysis, accumulates along with CO 2 , leading to acidification of the extracellular environment. In subcutaneous xenograft model of solid tumors, the average pH inside MM tumors was ~6.9 compared to pH of 7.4 outside of the tumors ( 85 ). It is the buildup of these acidic byproducts that necessitates activation of various acid/base regulatory salvage pathways within the cells, else the enzymes will be inactivated.…”

Section: Acid/base Regulationmentioning

confidence: 99%

Can Targeting Hypoxia-Mediated Acidification of the Bone Marrow Microenvironment Kill Myeloma Tumor Cells?

et al. 2021

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Multiple myeloma (MM) is an incurable cancer arising from malignant plasma cells that engraft in the bone marrow (BM). The physiology of these cancer cells within the BM microenvironment (TME) plays a critical role in MM development. These processes may be similar to what has been observed in the TME of other (non-hematological) solid tumors. It has been long reported that within the BM, vascular endothelial growth factor (VEGF), increased angiogenesis and microvessel density, and activation of hypoxia-induced transcription factors (HIF) are correlated with MM progression but despite a great deal of effort and some modest preclinical success the overall clinical efficacy of using anti-angiogenic and hypoxia-targeting strategies, has been limited. This review will explore the hypothesis that the TME of MM engrafted in the BM is distinctly different from non-hematological-derived solid tumors calling into question how effective these strategies may be against MM. We further identify other hypoxia-mediated effectors, such as hypoxia-mediated acidification of the TME, oxygen-dependent metabolic changes, and the generation of reactive oxygen species (ROS), that may prove to be more effective targets against MM.

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“…In osteolytic bone lesions in MM, therefore, the MM cell-OC interaction appears to create a highly acidic milieu by protons produced by OCs and lactate by proliferating glycolytic MM cells. We reported that acid activates the PI3K-Akt signaling to upregulate the acid sensor TRPV1 in MM cells, thereby forming a positive feedback loop between acid sensing and the PI3K-Akt survival signaling [86]. In addition, tumor acidity has been demonstrated to blunt cytotoxic effects of various chemotherapeutic agents as well as the activity of immune effecter cells [87,88].…”

Section: Targeting Of Osteoclastogenesis and Acidic Microenvironmentsmentioning

confidence: 99%

Myeloma–Bone Interaction: A Vicious Cycle via TAK1–PIM2 Signaling

Harada

Hiasa

Teramachi

et al. 2021

Cancers

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Multiple myeloma (MM) has a propensity to develop preferentially in bone and form bone-destructive lesions. MM cells enhance osteoclastogenesis and bone resorption through activation of the RANKL–NF-κB signaling pathway while suppressing bone formation by inhibiting osteoblastogenesis from bone marrow stromal cells (BMSCs) by factors elaborated in the bone marrow and bone in MM, including the soluble Wnt inhibitors DKK-1 and sclerostin, activin A, and TGF-β, resulting in systemic bone destruction with loss of bone. Osteocytes have been drawn attention as multifunctional regulators in bone metabolism. MM cells induce apoptosis in osteocytes to trigger the production of factors, including RANKL, sclerostin, and DKK-1, to further exacerbate bone destruction. Bone lesions developed in MM, in turn, provide microenvironments suited for MM cell growth/survival, including niches to foster MM cells and their precursors. Thus, MM cells alter the microenvironments through bone destruction in the bone where they reside, which in turn potentiates tumor growth and survival, thereby generating a vicious loop between tumor progression and bone destruction. The serine/threonine kinases PIM2 and TAK1, an upstream mediator of PIM2, are overexpressed in bone marrow stromal cells and osteoclasts as well in MM cells in bone lesions. Upregulation of the TAK1–PIM2 pathway plays a critical role in tumor expansion and bone destruction, posing the TAK1–PIM2 pathway as a pivotal therapeutic target in MM.

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A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration

Cited by 11 publications

References 50 publications

Unique anti‐myeloma activity by thiazolidine‐2,4‐dione compounds with Pim inhibiting activity

Unique anti‐myeloma activity by thiazolidine‐2,4‐dione compounds with Pim inhibiting activity

Can Targeting Hypoxia-Mediated Acidification of the Bone Marrow Microenvironment Kill Myeloma Tumor Cells?

Myeloma–Bone Interaction: A Vicious Cycle via TAK1–PIM2 Signaling

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