Pyrrole Hemithioindigo Antimitotics with Near-Quantitative Bidirectional Photoswitching Photocontrol Cellular Microtubule Dynamics with Single-Cell Precision

<div> <div> <div> <p>Photoswitchably bioactive reagents, known as “photopharmaceuticals”, promise powerful applications in high-precision biological research. Yet most photoswitch scaffolds cannot be quantitatively bidirectionally photoisomerised, so they suffer from residual background activity that can confound experiments. We rationally designed photopharmaceuticals using the emerging near-quantitative photoswitch pyrrole hemithioindigo (<b>PHTubs</b>), to isomer-specifically inhibit the cytoskeletal protein tubulin. These <b>PHTub</b> reagents allow simultaneous visible-light imaging and photoswitching in live cells, where they could be used for cell-precise photomodulation of microtubule dynamics, and photocontrol over cell cycle progression and cell death. This is, as far as we know, the first use of a hemithioindigo photopharmaceutical for high-spatiotemporal-resolution biological control in live cells. This work opens up new horizons for high-precision microtubule research using <b>PHTubs</b>; and shows the cellular applicability of the near-quantitative photoswitch pyrrole hemithioindigo as a valuable scaffold for photocontrol of a range of other biological targets. </p> </div> </div> </div>

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Molecular Mechanisms Underlying Yatein-Induced Cell-Cycle Arrest and Microtubule Destabilization in Human Lung Adenocarcinoma Cells

Cancers ◽

10.3390/cancers11091384 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1384 ◽

Cited By ~ 3

Author(s):

Shang-Tse Ho ◽

Chi-Chen Lin ◽

Yu-Tang Tung ◽

Jyh-Horng Wu

Keyword(s):

Cell Cycle ◽

Antitumor Activity ◽

Lung Adenocarcinoma ◽

Cell Cycle Progression ◽

Molecular Mechanisms ◽

Human Lung ◽

Microtubule Dynamics ◽

Cycle Progression ◽

Human Lung Adenocarcinoma

Yatein is an antitumor agent isolated from Calocedrus formosana Florin leaves extract. In our previous study, we found that yatein inhibited the growth of human lung adenocarcinoma A549 and CL1-5 cells by inducing intrinsic and extrinsic apoptotic pathways. To further uncover the effects and mechanisms of yatein-induced inhibition on A549 and CL1-5 cell growth, we evaluated yatein-mediated antitumor activity in vivo and the regulatory effects of yatein on cell-cycle progression and microtubule dynamics. Flow cytometry and western blotting revealed that yatein induces G2/M arrest in A549 and CL1-5 cells. Yatein also destabilized microtubules and interfered with microtubule dynamics in the two cell lines. Furthermore, we evaluated the antitumor activity of yatein in vivo using a xenograft mouse model and found that yatein treatment altered cyclin B/Cdc2 complex expression and significantly inhibited tumor growth. Taken together, our results suggested that yatein effectively inhibited the growth of A549 and CL1-5 cells possibly by disrupting cell-cycle progression and microtubule dynamics.

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(Z)-3,5,4′-Trimethoxystilbene Limits Hepatitis C and Cancer Pathophysiology by Blocking Microtubule Dynamics and Cell-Cycle Progression

Cancer Research ◽

10.1158/0008-5472.can-15-2722 ◽

2016 ◽

Vol 76 (16) ◽

pp. 4887-4896 ◽

Cited By ~ 7

Author(s):

Charles B. Nguyen ◽

Hari Kotturi ◽

Gulam Waris ◽

Altaf Mohammed ◽

Parthasarathy Chandrakesan ◽

...

Keyword(s):

Cell Cycle ◽

Hepatitis C ◽

Cell Cycle Progression ◽

Microtubule Dynamics ◽

Cycle Progression

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Extracellular Signal-regulated Kinase 1/2 Activity Is Not Required in Mammalian Cells during Late G2 for Timely Entry into or Exit from Mitosis

Molecular Biology of the Cell ◽

10.1091/mbc.e06-04-0284 ◽

2006 ◽

Vol 17 (12) ◽

pp. 5227-5240 ◽

Cited By ~ 23

Author(s):

Mio Shinohara ◽

Alexei V. Mikhailov ◽

Julio A. Aguirre-Ghiso ◽

Conly L. Rieder

Keyword(s):

Cell Cycle ◽

Mammalian Cells ◽

Cell Cycle Progression ◽

Spindle Assembly Checkpoint ◽

Spindle Assembly ◽

Live Cells ◽

Cycle Progression ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Sustained Inhibition

Extracellular signal-regulated kinase (ERK)1/2 activity is reported to be required in mammalian cells for timely entry into and exit from mitosis (i.e., the G2-mitosis [G2/M] and metaphase-anaphase [M/A] transitions). However, it is unclear whether this involvement reflects a direct requirement for ERK1/2 activity during these transitions or for activating gene transcription programs at earlier stages of the cell cycle. To examine these possibilities, we followed live cells in which ERK1/2 activity was inhibited through late G2 and mitosis. We find that acute inhibition of ERK1/2 during late G2 and through mitosis does not affect the timing of the G2/M or M/A transitions in normal or transformed human cells, nor does it impede spindle assembly, inactivate the p38 stress-activated checkpoint during late G2 or the spindle assembly checkpoint during mitosis. Using CENP-F as a marker for progress through G2, we also show that sustained inhibition of ERK1/2 transiently delays the cell cycle in early/mid-G2 via a p53-dependent mechanism. Together, our data reveal that ERK1/2 activity is required in early G2 for a timely entry into mitosis but that it does not directly regulate cell cycle progression from late G2 through mitosis in normal or transformed mammalian cells.

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Involvement of ERK1/2, p38 MAPK, and PI3K/Akt signaling pathways in the regulation of cell cycle progression by PTHrP in colon adenocarcinoma cells

Biochemistry and Cell Biology ◽

10.1139/bcb-2013-0106 ◽

2014 ◽

Vol 92 (4) ◽

pp. 305-315 ◽

Cited By ~ 8

Author(s):

Natalia Calvo ◽

María Julia Martín ◽

Ana Russo de Boland ◽

Claudia Gentili

Keyword(s):

Cell Cycle ◽

Signaling Pathways ◽

P38 Mapk ◽

Cell Cycle Progression ◽

Regulatory Protein ◽

Cyclin D3 ◽

Live Cells ◽

Cell Cycle Regulators ◽

Cycle Progression ◽

A Cell

Parathyroid hormone-related peptide (PTHrP) is distributed in most fetal and adult tissues, and its expression correlates with the severity of colon carcinoma. Recently we obtained evidence that in Caco-2 cells, a cell line from human colorectal adenocarcinoma, exogenous PTHrP increases the number of live cells, via ERK1/2, p38 MAPK, and PI3-kinase and induces the expression of cyclin D1, a cell cycle regulatory protein. In this study, we further investigated the role of PTHrP in the regulation of the cell cycle progression in these intestinal cells. Flow cytometry analysis revealed that PTHrP treatment diminishes the number of cells in the G0/G1 phase and increases the number in both S and G2/M phases. The hormone increases the expression of CDK6 and diminishes the amount of negative cell cycle regulators p27Kip1, p15INK4B, and p53. However, PTHrP does not modify the expression of cyclin D3, CDK4, and p16INK4A. In addition, inhibitors of ERK1/2 (PD98059), p38 MAPK (SB203580), and PI3Kinase (LY294002) reversed PTHrP response in Caco-2 cells. Taken together, our results suggest that PTHrP positively modulates cell cycle progression and changes the expression of proteins involved in cell cycle regulation via ERK1/2, p38 MAPK, and PI3K signaling pathways in Caco-2 cells.

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