Alex X.F. Wong

Supplementary Data containing Supplementary Methods, 10 Supplementary Figures and 5 Supplementary Tables from Autophagy Governs Protumorigenic Effects of Mitotic Slippage–induced Senescence

Rekha Jakhar Monique Luijten Alex X.F. Wong Bing Cheng Ke Guo

S1. Post-slippage cells arrest at G1 as tetraploid multinucleated cells. S2. Correlation of multinucleation and senescence post-slippage in response to various anti-mitotic drugs. S3. In vivo association of senescence and anti-mitotic drug treatment. S4. Post-slippage cells increase expression of factors associated with senescence and SASP. S5. SASP factors from post-slippage cells do not affect proliferation of neighbouring cells. S6. Autophagy mediates senescence. S7. Autophagy does not modulate cell fate during prolonged mitotic arrest. S8. Autophagy-dependent IL-1β and IL-8 expression mediate cell invasiveness in a paracrine manner. S9. Silencing of p53 increases post-slippage cell death. S10. p53 status determines synergistic effect of microtubule poisons and autophagy inhibition. Table S1. List of differentially regulated proteins after 48 h Noc treatment detected by SILAC mass spectrometry. Table S2. List of antibodies. Table S3. List of chemicals. Table S4. List of primers. Table S5. Quantitative H scoring method

Senescence

Slippage

10.1158/1541-7786.22515274.v1

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Data from Autophagy Governs Protumorigenic Effects of Mitotic Slippage–induced Senescence

Rekha Jakhar Monique Luijten Alex X.F. Wong Bing Cheng Ke Guo

<div>AbstractThe most commonly utilized class of chemotherapeutic agents administered as a first-line therapy are antimitotic drugs; however, their clinical success is often impeded by chemoresistance and disease relapse. Hence, a better understanding of the cellular pathways underlying escape from cell death is critical. Mitotic slippage describes the cellular process where cells exit antimitotic drug-enforced mitotic arrest and “slip” into interphase without proper chromosome segregation and cytokinesis. The current report explores the cell fate consequence following mitotic slippage and assesses a major outcome following treatment with many chemotherapies, therapy-induced senescence. It was found that cells postslippage entered senescence and could impart the senescence-associated secretory phenotype (SASP). SASP factor production elicited paracrine protumorigenic effects, such as migration, invasion, and vascularization. Both senescence and SASP factor development were found to be dependent on autophagy. Autophagy induction during mitotic slippage involved the autophagy activator AMPK and endoplasmic reticulum stress response protein PERK. Pharmacologic inhibition of autophagy or silencing of autophagy-related ATG5 led to a bypass of G1 arrest senescence, reduced SASP-associated paracrine tumorigenic effects, and increased DNA damage after S-phase entry with a concomitant increase in apoptosis. Consistent with this, the autophagy inhibitor chloroquine and microtubule-stabilizing drug paclitaxel synergistically inhibited tumor growth in mice. Sensitivity to this combinatorial treatment was dependent on p53 status, an important factor to consider before treatment.Implications: Clinical regimens targeting senescence and SASP could provide a potential effective combinatorial strategy with antimitotic drugs. Mol Cancer Res; 16(11); 1625–40. ©2018 AACR.</div>

Senescence

Mitotic catastrophe

10.1158/1541-7786.c.6541024

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Supplementary Data containing Supplementary Methods, 10 Supplementary Figures and 5 Supplementary Tables from Autophagy Governs Protumorigenic Effects of Mitotic Slippage–induced Senescence

Rekha Jakhar Monique Luijten Alex X.F. Wong Bing Cheng Ke Guo

S1. Post-slippage cells arrest at G1 as tetraploid multinucleated cells. S2. Correlation of multinucleation and senescence post-slippage in response to various anti-mitotic drugs. S3. In vivo association of senescence and anti-mitotic drug treatment. S4. Post-slippage cells increase expression of factors associated with senescence and SASP. S5. SASP factors from post-slippage cells do not affect proliferation of neighbouring cells. S6. Autophagy mediates senescence. S7. Autophagy does not modulate cell fate during prolonged mitotic arrest. S8. Autophagy-dependent IL-1β and IL-8 expression mediate cell invasiveness in a paracrine manner. S9. Silencing of p53 increases post-slippage cell death. S10. p53 status determines synergistic effect of microtubule poisons and autophagy inhibition. Table S1. List of differentially regulated proteins after 48 h Noc treatment detected by SILAC mass spectrometry. Table S2. List of antibodies. Table S3. List of chemicals. Table S4. List of primers. Table S5. Quantitative H scoring method

Senescence

Slippage

10.1158/1541-7786.22515274

Cite

Citations (0)

Data from Autophagy Governs Protumorigenic Effects of Mitotic Slippage–induced Senescence

Rekha Jakhar Monique Luijten Alex X.F. Wong Bing Cheng Ke Guo

<div>AbstractThe most commonly utilized class of chemotherapeutic agents administered as a first-line therapy are antimitotic drugs; however, their clinical success is often impeded by chemoresistance and disease relapse. Hence, a better understanding of the cellular pathways underlying escape from cell death is critical. Mitotic slippage describes the cellular process where cells exit antimitotic drug-enforced mitotic arrest and “slip” into interphase without proper chromosome segregation and cytokinesis. The current report explores the cell fate consequence following mitotic slippage and assesses a major outcome following treatment with many chemotherapies, therapy-induced senescence. It was found that cells postslippage entered senescence and could impart the senescence-associated secretory phenotype (SASP). SASP factor production elicited paracrine protumorigenic effects, such as migration, invasion, and vascularization. Both senescence and SASP factor development were found to be dependent on autophagy. Autophagy induction during mitotic slippage involved the autophagy activator AMPK and endoplasmic reticulum stress response protein PERK. Pharmacologic inhibition of autophagy or silencing of autophagy-related ATG5 led to a bypass of G1 arrest senescence, reduced SASP-associated paracrine tumorigenic effects, and increased DNA damage after S-phase entry with a concomitant increase in apoptosis. Consistent with this, the autophagy inhibitor chloroquine and microtubule-stabilizing drug paclitaxel synergistically inhibited tumor growth in mice. Sensitivity to this combinatorial treatment was dependent on p53 status, an important factor to consider before treatment.Implications: Clinical regimens targeting senescence and SASP could provide a potential effective combinatorial strategy with antimitotic drugs. Mol Cancer Res; 16(11); 1625–40. ©2018 AACR.</div>

Senescence

Mitotic catastrophe

10.1158/1541-7786.c.6541024.v1

Cite

Citations (0)

Alex X.F. Wong

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H-Index

i-10 index

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H-Index

i-10 index