Bafilomycin A1 induces apoptosis in the human pancreatic cancer cell line Capan-1

Ohta, Tetsuo; Arakawa, Hajime; Futagami, Fumio; Fushida, Sachio; Kitagawa, Hirohisa; Kayahara, Masato; Nagakawa, Takukazu; Miwa, Koichi; Kurashima, Kazuyoshi; Numata, Masayuki; Kitamura, Yukisato; Terada, Tadashi; Ohkuma, Shoji

doi:10.1002/(sici)1096-9896(199807)185:3<324::aid-path72>3.0.co;2-9

Cited by 78 publications

(51 citation statements)

References 15 publications

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“…Hygrobafilomycin and growth inhibition of the xenograft in vivo. 27 The compounds show selective cytotoxicity with above average activity in 12.5-17.5% of the cell lines as tested ( Table 2). The lower cytotoxic activity of compound 3 (mean IC 50 86.3 nM) points to a crucial role of the tetrahydropyran ring system, as this was found for the vacuolar ATPase inhibition effect of bafilomycin derivatives.…”

Section: Resultsmentioning

confidence: 98%

Hygrobafilomycin, a cytotoxic and antifungal macrolide bearing a unique monoalkylmaleic anhydride moiety, from Streptomyces varsoviensis

et al. 2010

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A new bafilomycin-type macrolide, named hygrobafilomycin (6), was isolated by a bioassay-guided selection and fractionation from a terrestrial actinomycete, Streptomyces varsoviensis, along with three known derivatives, bafilomycin D (3), C1 (4) and C2 (5). The structure of hygrobafilomycin was fully established by MS and NMR analyses, revealing a hygrolidin-bafilomycin hybrid with an unusual monoalkylmaleic anhydride moiety. Hygrobafilomycin (6) shows strong antifungal, antiproliferative and cytotoxic activities. In a panel of 40 tumor cell lines, compound 6 shows high cytotoxic potency (mean IC 50 ¼5.3 nM).

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Section: Resultsmentioning

confidence: 98%

Hygrobafilomycin, a cytotoxic and antifungal macrolide bearing a unique monoalkylmaleic anhydride moiety, from Streptomyces varsoviensis

et al. 2010

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“…8 In contrast, autophagy was important for long-term NP cell survival, possibly due to overall inhibition of the protein degradation machinery and accumulation of misfolded proteins resulting in ER stress. 74,75 It is important to note that aberrant changes in autophagy are involved in the pathogenesis of many diseases as well as normal aging. 76,77 An altered level of autophagy during intervertebral disc degeneration and aging has been reported.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling

et al. 2016

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Nucleus pulposus (NP) cells reside in the avascular and hypoxic microenvironment of intervertebral discs. Importantly, many activities related to survival and function of NP cells are controlled by the HIF-family of transcription factors. We hypothesize that NP cells adapt to their hypoxic niche through modulation of macroautophagy/autophagy. In various cell types, hypoxia induces autophagy in a HIF1A-dependent fashion; however, little is known about hypoxic regulation of autophagy in NP cells. Hypoxia increases the number of autophagosomes as seen by TEM analysis and LC3-positive puncta in NP cells. Hypoxic induction of autophagy was also demonstrated by a significantly higher number of autophagosomes and smaller change in autolysosomes in NP cells expressing tandem-mCherry-EGFP-LC3B. Increased LC3-II levels were not accompanied by a concomitant increase in BECN1 or the ATG12-ATG5 complex. In addition, ULK1 phosphorylation at Ser757 and Ser777 responsive to MTOR and AMPK, respectively, was not affected in hypoxia. Interestingly, when MTOR activity was inhibited by rapamycin or Torin1, LC3-II levels did not change, suggesting a novel MTOR-independent regulation. Noteworthy, while silencing of HIF1A affected hypoxic induction of BNIP3, it did not affect LC3-II levels, indicating hypoxia-induced autophagy is HIF1-independent. Importantly, there was no change in the number of LC3-positive autophagosomes in NP-specific Hif1a null mice. Finally, inhibition of autophagic flux did not affect the glycolytic metabolism of NP cells, suggesting a possible nonmetabolic role of autophagy. Taken together, our study for the first time shows that NP cells regulate autophagy in a noncanonical fashion independent of MTOR and HIF1A signaling.

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“…However, baf A1 not only inhibits V-ATPase but also functions as an ionophore that causes influx of potassium into mitochondria. This can be lethal for various cells, including cancer and osteoclast-like cells, [46][47][48] but most importantly this function blurs interpretation of experimental data because intracellular ion homeostasis is disturbed. We are not aware of such effects of 4AD, suggesting that 4AD and other novel V-ATPase inhibitors, such as new derivatives of baf A1 that selectively inhibit V-ATPases, 49 represent alternatives to baf A1 as molecular tools for studying cellular trafficking processes.…”

Section: Discussionmentioning

confidence: 99%

Small-Molecule Screening Identifies Modulators of Aquaporin-2 Trafficking

Bogum

Faust

Zühlke

et al. 2013

Journal of the American Society of Nephrology

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In the principal cells of the renal collecting duct, arginine vasopressin (AVP) stimulates the synthesis of cAMP, leading to signaling events that culminate in the phosphorylation of aquaporin-2 water channels and their redistribution from intracellular domains to the plasma membrane via vesicular trafficking. The molecular mechanisms that control aquaporin-2 trafficking and the consequent water reabsorption, however, are not completely understood. Here, we used a cell-based assay and automated immunofluorescence microscopy to screen 17,700 small molecules for inhibitors of the cAMP-dependent redistribution of aquaporin-2. This approach identified 17 inhibitors, including 4-acetyldiphyllin, a selective blocker of vacuolar H + -ATPase that increases the pH of intracellular vesicles and causes accumulation of aquaporin-2 in the Golgi compartment. Although 4-acetyldiphyllin did not inhibit forskolin-induced increases in cAMP formation and downstream activation of protein kinase A (PKA), it did prevent cAMP/PKAdependent phosphorylation at serine 256 of aquaporin-2, which triggers the redistribution to the plasma membrane. It did not, however, prevent cAMP-induced changes to the phosphorylation status at serines 261 or 269. Last, we identified the fungicide fluconazole as an inhibitor of cAMP-mediated redistribution of aquaporin-2, but its target in this pathway remains unknown. In conclusion, our screening approach provides a method to begin dissecting molecular mechanisms underlying AVP-mediated water reabsorption, evidenced by our identification of 4-acetyldiphyllin as a modulator of aquaporin-2 trafficking.

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Bafilomycin A1 induces apoptosis in the human pancreatic cancer cell line Capan-1

Cited by 78 publications

References 15 publications

Hygrobafilomycin, a cytotoxic and antifungal macrolide bearing a unique monoalkylmaleic anhydride moiety, from Streptomyces varsoviensis

Hygrobafilomycin, a cytotoxic and antifungal macrolide bearing a unique monoalkylmaleic anhydride moiety, from Streptomyces varsoviensis

Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling

Small-Molecule Screening Identifies Modulators of Aquaporin-2 Trafficking

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