Identification of PIKfyve kinase as a target in multiple myeloma

Campos, Cecília Bonolo de; Zhu, Yuan Xiao; Sepetov, Nikolai F.; Romanov, Sergei; Bruins, Laura A.; Shi, Chao; Stein, Caleb K.; Petit, Joachim; Polito, Alysia; Sharik, Meaghen E; Meermeier, Erin W.; Ahmann, Gregory; Armenta, Ilsel D Lopez; Kruse, Jonas; Bergsagel, P. Leif; Chesi, Marta; Meurice, Nathalie; Braggio, Esteban; Stewart, A. Keith

doi:10.3324/haematol.2019.222729

Cited by 27 publications

(54 citation statements)

References 44 publications

(57 reference statements)

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“…Monodansylcadaverine, a fluorescent pigment, is typically used to detect the occurrence of autophagy (Weiss-Sadan et al, 2019;de Campos et al, 2020). We identified that the fluorescence intensity of MDC was clearly increased after 10 μM Cr (VI) treatment (Figures 3A,B), suggestive of Cr (VI)-induced autophagy in SSCs/progenitors.…”

Section: Cr (Vi) Induced Mitochondrial Dynamic Imbalance and Mitophagy In Sscs/ Progenitorsmentioning

confidence: 90%

Melatonin Attenuates Chromium (VI)-Induced Spermatogonial Stem Cell/Progenitor Mitophagy by Restoration of METTL3-Mediated RNA N6-Methyladenosine Modification

Yang

et al. 2021

Front. Cell Dev. Biol.

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Spermatogonial stem cells (SSCs) are the basis of spermatogenesis, and any damage to SSCs may result in spermatogenic disorder and male infertility. Chromium (Cr) (VI) is a proven toxin, mutagen, and carcinogen, perpetually detrimental to environmental organisms due to its intricate and enduring detoxification process in vivo. Despite this, the deleterious effects of Cr (VI) on SSCs and the underlying mechanisms remain poorly understood. In this study, we identified that Cr (VI) impaired male reproductive system in mouse testes and induced mitochondrial dynamic imbalance and mitophagy in SSCs/progenitors. Cr (VI) also downregulated the RNA N6-methyladenosine (m6A) modification levels in mitochondrial dynamic balance and mitophagy genes in SSCs/progenitors. Inspiringly, the toxic effects of Cr (VI) could be relieved by melatonin pretreatment. Melatonin alleviated Cr (VI)-induced damage to male reproductive system and autophagy in mouse testes. Melatonin also attenuated Cr (VI)-induced cell viability loss and reactive oxygen species (ROS) generation, as well as mitochondrial dynamic disorders and mitophagy in SSCs/progenitors. The protective roles of melatonin against Cr (VI)-induced mitophagy were exerted by restoration of METTL3-mediated RNA m6A modification and activation of mitochondrial fusion proteins MFN2 and OPA1, as well as inhibition of the mitophagy BNIP3/NIX receptor pathway. Thus, our study provides novel insights into the molecular mechanisms for RNA m6A modification underlying the gene regulatory network responsible for mitochondrial dynamic balance, and also lays new experimental groundwork for treatment of Cr (VI)-induced damage to male fertility.

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Section: Cr (Vi) Induced Mitochondrial Dynamic Imbalance and Mitophagy In Sscs/ Progenitorsmentioning

confidence: 90%

Melatonin Attenuates Chromium (VI)-Induced Spermatogonial Stem Cell/Progenitor Mitophagy by Restoration of METTL3-Mediated RNA N6-Methyladenosine Modification

Yang

et al. 2021

Front. Cell Dev. Biol.

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“…Among the differentially sensitive drugs, we noted novel MM target classes, notably PIKfyve inhibitors, which were active in over 90% of HMCLs. Data specifically focused on PIKfyve inhibition in hematological malignancies has been subsequently published [45][46][47] .…”

Section: Specificity Of the MM Screening Panelmentioning

confidence: 99%

“Direct to Drug” screening as a precision medicine tool in multiple myeloma

et al. 2020

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Seventy-six FDA-approved oncology drugs and emerging therapeutics were evaluated in 25 multiple myeloma (MM) and 15 non-Hodgkin's lymphoma cell lines and in 113 primary MM samples. Ex vivo drug sensitivities were mined for associations with clinical phenotype, cytogenetic, genetic mutation, and transcriptional profiles. In primary MM samples, proteasome inhibitors, dinaciclib, selinexor, venetoclax, auranofin, and histone deacetylating agents had the broadest cytotoxicity. Of interest, newly diagnosed patient samples were globally less sensitive especially to bromodomain inhibitors, inhibitors of receptor tyrosine kinases or non-receptor kinases, and DNA synthesis inhibitors. Clustering demonstrated six broad groupings of drug sensitivity linked with genomic biomarkers and clinical outcomes. For example, our findings mimic clinical observations of increased venetoclax responsiveness in t(11;14) patients but also identify an increased sensitivity profile in untreated patients, standard genetic risk, low plasma cell S-Phase, and in the absence of Gain(1q) and t(4;14). In contrast, increased ex vivo responsiveness to selinexor was associated with biomarkers of poor prognosis and later relapse patients. This "direct to drug" screening resource, paired with functional genomics, has the potential to successfully direct appropriate individualized therapeutic approaches in MM and to enrich clinical trials for likely responders.

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“…It was demonstrated that cytotoxicity of PIKfyve inhibitors requires growth factor/Akt suppression and excessive cytoplasmic vacuolation (Ikonomov et al, 2018). PIKfyve inhibitors disrupted lysosomal function, autophagic flux, and the high basal necessity of autophagy in plasma cells and multiple myeloma cells (de Campos et al, 2020). Therefore, inhibition of PIKfyve was suggested as a novel target for multiple myeloma.…”

Section: Discussionmentioning

confidence: 99%

The effects of PIKfyve inhibitor YM201636 on claudins and malignancy potential of nonsmall cell cancer cells

Dogan¹,

Düzgün²,

Yildirim³

et al. 2021

Turk J Biol

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PIKfyve is an evolutionarily conserved lipid and protein kinase enzyme that has pleiotropic cellular functions. The aim of the present study was to investigate the effects of phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) inhibitor, YM201636, on nonsmall cell lung cancer (NSCLC) cells growth, tumorigenicity, and claudin (CLDN) expressions. Three NSCLC cell lines (Calu-1, H1299 and HCC827) were used to compare the effects of YM201636. Cytotoxic effects of YM201636 were analysed using XTT assay. Malignancy potential of cells assesses with wound healing and soft agar colony-forming assays. mRNA and protein expressions of claudins were analysed by qRT-PCR and immunofluorescence staining. Our results revealed that YM201636 inhibited the proliferation and malignancy potential of Calu-1, H1299, and HCC827 cells in a dose-dependent manner. After YM201636 treatment CLDN1, -3 and -5 expressions increased significantly in HCC827 cells. CLDN3 and -5 expressions also significantly increased in Calu1 cell line. YM201636 treatment significantly reduced the CLDN1 and increased the CLDN5 expression in H1299 cells. Immunofluorescence staining of CLDN1, -3 and -5 proteins showed a significant increase after YM201636 treatment. Besides, YM201636 induced EGFR mRNA expression in all NSCLC cell lines. Our results have shown that YM201636 inhibits tumorigenicity of NSCLC cells. Furthermore, estimated glomerular filtration rate (EGFR) pathway is important signalling involved in the regulation of claudins. Understanding the mechanisms of PIKfyve inhibitors may improve cancer treatment particularly for EGFR overactivated NSCLC.

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Identification of PIKfyve kinase as a target in multiple myeloma

Cited by 27 publications

References 44 publications

Melatonin Attenuates Chromium (VI)-Induced Spermatogonial Stem Cell/Progenitor Mitophagy by Restoration of METTL3-Mediated RNA N6-Methyladenosine Modification

Melatonin Attenuates Chromium (VI)-Induced Spermatogonial Stem Cell/Progenitor Mitophagy by Restoration of METTL3-Mediated RNA N6-Methyladenosine Modification

“Direct to Drug” screening as a precision medicine tool in multiple myeloma

The effects of PIKfyve inhibitor YM201636 on claudins and malignancy potential of nonsmall cell cancer cells

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