Vacuolin‐1 inhibits autophagy by impairing lysosomal maturation via <scp>PIK</scp>fyve inhibition

Sano, Osamu; Kazetani, Ken-ichi; Funata, Masaaki; Fukuda, Yasunori; Matsui, Junji; Iwata, Hidehisa

doi:10.1002/1873-3468.12195

Cited by 43 publications

(40 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among synergistic compounds selected from screening, Bax channel blocker was subjected to further investigation because it was a hit compound from the autophagy inhibitor screening campaign that we carried out previously [26] (Fig 2B, green plot). Bax channel blocker (3 μM) potentiated the growth inhibitory activity of T-3764518 in HCT-116 cells (Fig 3A and Panel A in S2 Fig).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Feedback activation of AMPK-mediated autophagy acceleration is a key resistance mechanism against SCD1 inhibitor-induced cell growth inhibition

et al. 2017

Self Cite

View full text Add to dashboard Cite

Elucidating the bioactive compound modes of action is crucial for increasing success rates in drug development. For anticancer drugs, defining effective drug combinations that overcome resistance improves therapeutic efficacy. Herein, by using a biologically annotated compound library, we performed a large-scale combination screening with Stearoyl-CoA desaturase-1 (SCD1) inhibitor, T-3764518, which partially inhibits colorectal cancer cell proliferation. T-3764518 induced phosphorylation and activation of AMPK in HCT-116 cells, which led to blockade of downstream fatty acid synthesis and acceleration of autophagy. Attenuation of fatty acid synthesis by small molecules suppressed the growth inhibitory effect of T-3764518. In contrast, combination of T-3764518 with autophagy flux inhibitors synergistically inhibited cellular proliferation. Experiments using SCD1 knock-out cells validated the results obtained with T-3764518. The results of our study indicated that activation of autophagy serves as a survival signal when SCD1 is inhibited in HCT-116 cells. Furthermore, these findings suggest that combining SCD1 inhibitor with autophagy inhibitors is a promising anticancer therapy.

show abstract

Section: Resultsmentioning

confidence: 99%

“…AZD8055 [mammalian target of rapamycin (mTORC) inhibitor] and STA5326 (PIKfyve inhibitor) were purchased from Selleck (Houston, TX, USA). Vacuolin-1 (PIKfyve inhibitor) [26] was purchased from Merck Millipore (Darmstadt, Germany). GSK2194069 [fatty acid synthase (FASN) inhibitor] was purchased from Chemexpress Co., Ltd. (Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

Feedback activation of AMPK-mediated autophagy acceleration is a key resistance mechanism against SCD1 inhibitor-induced cell growth inhibition

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…There are three primary forms of autophagy: chaperonemediated autophagy, microautophagy and macroautophagy (24)(25)(26)(27)(28). During the process of macroautophagy, the sequestering vesicles, termed autophagosomes, fuse with the lysosome or vacuole resulting in the delivery of an inner vesicle (autophagic body) into the lumen of the degradative compartment (29)(30)(31).…”

Section: Autophagy and Apoptosis In The Bm-mscs Therapy Towards Myocamentioning

confidence: 99%

Into the eyes of bone marrow-derived mesenchymal stem cells therapy for myocardial infarction and other diseases

Li¹,

Qu²

2017

Stem Cell Investig.

View full text Add to dashboard Cite

Applications of bone marrow-derived mesenchymal stem cells (BM-MSCs) have been documented for diseases occur in the sports system, the central nervous system, the cardiovascular system etc. However, poor viability of donor stem cells after transplantation limits their therapeutic efficiency. Although the autophagy theory has been reported, the underlying mechanisms are still poorly understood. Isolation and culture methods of mesenchymal stem cells are currently concentrate on four ways. Overall, BM-MSCs have both important research significance and clinical application value in cell replacement therapy, gene therapy and reconstruction of tissues as well as organs especially for myocardial infarction (MI). In this article, we review the biological characteristics of BM-MSCs and its research progress especially in MI. bone marrow which has aroused people's interest (1,4,5). Furthermore, BM-MSCs can act as support hematopoietic cells, promoting the growth of hematopoietic stem cells. Above all, BM-MSCs have broad application prospects in tissue engineering, cell transplantation and gene therapy because of the advantages of easy separation, amplification and easy operation in vitro and in vivo (6)(7)(8)(9). Taken together, BM-MSCs have important research significance and clinical application value in cell replacement therapy, gene therapy and tissue regeneration. In this article we review the latest progress, limitation as well as clinical application of BMMSCs. Isolation of BM-MSCsBM-MSCs are obtained mainly from bone marrow aspiration, while human BM-MSCs are generally drawn from the anterior superior iliac spine (10). They are also available from the tibia, femur, sternum, lumbar spine. The acquisition sites of BM-MSCs in large animals are the same as humans, however, rabbits' BM-MSCs need to be extracted in the middle of the tibia or femur bone marrow (11-13). The proportion of BM-MSCs nucleated cell population accounts for less than 0.0001% of them, however they can easily be isolated and expanded by using certain cell culture techniques (10). Stro-1 monoclonal antibody is usually used to isolate BM-MSCs which grow by attaching to the wall in laminin adhesion culture plate with low concentration of serum and CD45-/A-glycoproteins (14). In the past, BM-MSCs isolation methods were mainly concentrated on density gradient centrifugation method, differential adherence screening method, flow cytometry sorting method as well as immune beads method (15). However, high purity of BM-MSCs cannot be obtained by the four kinds of separation methods as described above. Nowadays, selecting the appropriate factor based on different reactivity of BM-MSCs to growth factors, to stimulate the proliferation, obtaining a higher proportion the mesenchymal stem cells has been regarded as a more accurate isolation method. Meanwhile, the new method of using 3 microns diameter plastic petri dish to screen BMMSCs, whose homogeneity are greater than 98%, with capacity of proliferation, self-renewal and have the potential to diff...

show abstract

“…Pharmacological inhibition of PIKfyve by small chemical compounds, including vacuolin-1 and apilimod is known to cause enlarged lysosomes in several cell types, including mast cells and macrophages. 50,74,75 Here, we show that inhibition of PIKfyve by three different chemical compounds caused enlargement of the lysosomal compartment. Importantly, this was associated with increased granzyme B expression, increased Ca 2+ -flux, and more potent effector function.…”

Section: Trpml1-mediated Modulation Of Secretory Granules In Nk Cellsmentioning

confidence: 64%

Modulation of Secretory Lysosomes During NK Cell Education Leads to Accumulation of Granzyme B and Enhanced Functional Potential

Goodridge

Jacobs

Satersmoen

et al. 2018

Preprint

View full text Add to dashboard Cite

Inhibitory signaling during natural killer (NK) cell education translates into increased responsiveness to activation; however the intracellular mechanism for functional tuning by inhibitory receptors remains unclear. We found that educated NK cells expressing self-MHC specific inhibitory killer cell immunoglobulin-like receptors (KIR) show accumulation of granzyme B, localized in dense-core secretory lysosomes, converged close to the centrosome. This discrete morphological phenotype persists in self-KIR+ NK cells independently of transcriptional programs that regulate effector function, metabolism and lysosomal biogenesis. The granzymeB dense, large secretory lysosomes in self-KIR+ NK cells were efficiently released upon target cell recognition, contributing to their enhanced cytotoxic capacity. Secretory lysosomes are part of the acidic lysosomal compartment, which has been shown to channel calcium and mediate intracellular signalling in several cell types. Interference of signaling from acidic Ca2+ stores in primary NK cells reduced both target-specific Ca2+-flux, degranulation and cytokine production. Furthermore, inhibition of PI(3,5)P2 synthesis or genetic silencing of the PI(3,5)P2-regulated lysosomal Ca2+-channel TRPML1 led to increased levels of granzyme B and enhanced functional potential. These results indicate an intrinsic role for lysosomal homeostasis in NK cell education.

show abstract

Vacuolin‐1 inhibits autophagy by impairing lysosomal maturation via PIKfyve inhibition

Cited by 43 publications

References 33 publications

Feedback activation of AMPK-mediated autophagy acceleration is a key resistance mechanism against SCD1 inhibitor-induced cell growth inhibition

Feedback activation of AMPK-mediated autophagy acceleration is a key resistance mechanism against SCD1 inhibitor-induced cell growth inhibition

Into the eyes of bone marrow-derived mesenchymal stem cells therapy for myocardial infarction and other diseases

Modulation of Secretory Lysosomes During NK Cell Education Leads to Accumulation of Granzyme B and Enhanced Functional Potential

Contact Info

Product

Resources

About