A genome-wide enrichment screen identifies NUMA1-loss as a resistance mechanism against mitotic cell-death induced by BMI1 inhibition

AbstractBMI1 is a core protein of the polycomb repressive complex 1 (PRC1) that is overexpressed in several cancer types, making it a promising target for cancer therapies. However, the underlying mechanisms and interactions associated with BMI1-induced tumorigenesis are often context-dependent and complex. Here, we performed a drug resistance screen on mutagenized human haploid HAP1 cells treated with the BMI1 inhibitor PTC-318 to find new genetic and mechanistic features associated with BMI1-dependent cancer cell proliferation. Our screen identified NUMA1-mutations as the most significant inducer of PTC-318 cell death resistance. Independent validations on NUMA1-proficient HAP1 and non-small cell lung cancer cell lines exposed to BMI1 inhibition by PTC-318 or BMI1 knockdown resulted in cell death following mitotic arrest. Interestingly, cells with CRISPR-Cas9 derived NUMA1 knockout also showed a mitotic arrest phenotype following BMI1 inhibition but, contrary to cells with wildtype NUMA1, these cells were resistant to BMI1-dependent cell death. The current study brings new insights to BMI1 inhibition-induced mitotic lethality in cancer cells and presents a previously unknown role for NUMA1 in this process.

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A genome-wide enrichment screen identifies NUMA1-loss as a resistance mechanism against mitotic cell-death induced by BMI1 inhibition

PLoS ONE ◽

10.1371/journal.pone.0227592 ◽

2020 ◽

Vol 15 (4) ◽

pp. e0227592

Author(s):

Santiago Gisler ◽

Ana Rita R. Maia ◽

Gayathri Chandrasekaran ◽

Jawahar Kopparam ◽

Maarten van Lohuizen

Keyword(s):

Cell Death ◽

Resistance Mechanism ◽

Mitotic Cell ◽

Genome Wide ◽

A Genome

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Dual Function Microtubule- and Mitochondria-Associated Proteins Mediate Mitotic Cell Death

Analytical Cellular Pathology ◽

10.1155/2009/783817 ◽

2009 ◽

Vol 31 (5) ◽

pp. 393-405

Author(s):

Leyuan Liu ◽

Rui Xie ◽

Chaofeng Yang ◽

Wallace L. McKeehan

Keyword(s):

Cell Death ◽

Mitotic Cell ◽

Mitotic Arrest ◽

Dual Function ◽

Associated Proteins ◽

Irreversible Aggregation ◽

The Common ◽

Spindle Microtubules ◽

Segregation Of Chromosomes ◽

Mitotic Cells

Background: Survival and evolution of aneuploid cells after an asymmetric segregation of chromosomes at mitosis may be the common initiating event and underlying cause of the genetic diversity and adaptability of cancers. We hypothesize that mechanisms exist to detect impending aneuploidy and prevent it before completion of an aberrant mitosis.Methods: The distribution of isoforms of C19ORF5, an interactive partner with mitochondria-associated LRPPRC and tumor suppressor RASSF1A, state of spindle microtubules and mitochondrial aggregation was analyzed in synchronized mitotic cells and cells stalled in mitosis after treatment with paclitaxel.Results: C19ORF5 distributed broadly across the mitotic spindle and reversibly accumulated during reversible mitotic arrest. Prolonged stabilization of microtubules caused an accumulation of a C19ORF5 product with dual MAP and MtAP properties that caused irreversible aggregation of mitochondria and death of mitotic cells.Conclusions: Dual function microtubule-associated (MAP) and mitochondria-associated (MtAP) proteins generated by prolonged mitotic arrest trigger mitochondrial-induced mitotic cell death. This is a potential mechanism to prevent minimal survivable aneuploidy resulting from an aberrant cell division and cancers in general at their earliest common origin.

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Ferroptosis: A New Promising Target for Lung Cancer Therapy

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/8457521 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Rui Xiong ◽

Ruyuan He ◽

Bohao Liu ◽

Wenyang Jiang ◽

Bo Wang ◽

...

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Lipid Peroxides ◽

Cancer Therapies ◽

Biological Processes ◽

Promising Target ◽

Underlying Basis ◽

Lung Cancer Therapy ◽

New Type ◽

Growth Of Tumor

Ferroptosis is a new type of regulatory cell death that differs from autophagy, apoptosis, necrosis, and pyroptosis; it is caused primarily by the accumulation of iron and lipid peroxides in the cell. Studies have shown that many classical signaling pathways and biological processes are involved in the process of ferroptosis. In recent years, investigations have revealed that ferroptosis plays a crucial role in the progression of tumors, especially lung cancer. In particular, inducing ferroptosis in cells can inhibit the growth of tumor cells, thereby reversing tumorigenesis. In this review, we summarize the characteristics of ferroptosis from its underlying basis and role in lung cancer and provide possible applications for it in lung cancer therapies.

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Regulation of Bax-dependent apoptosis by mitochondrial deubiquitinase USP30

Cell Death Discovery ◽

10.1038/s41420-021-00599-6 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Ding Yan ◽

Xiaofen Li ◽

Qianqian Yang ◽

Qingtian Huang ◽

Leyi Yao ◽

...

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Cancer Cells ◽

Cancer Cell ◽

Lung Cancer Cells ◽

Cancer Therapies ◽

Metal Compounds ◽

Cancer Cell Death ◽

Bax Protein ◽

Synthetic Derivative

AbstractDeubiquitinates (DUBs) have been suggested as novel promising targets for cancer therapies. Accumulating experimental evidence suggests that some metal compounds have the potential to induce cancer cell death via inhibition of DUBs. We previously reported that auranofin, a gold(I)-containing agent used for the treatment of rheumatoid arthritis in clinics, can induce cell death by inhibiting proteasomal DUBs in a series of cancer cell lines. Unfortunately, currently available gold compounds are not potent in inhibiting DUBs. Here, we report that: (i) aumdubin, a synthetic derivative of auranofin, exhibited stronger DUB-inhibiting and apoptosis-inducing activities than auranofin in lung cancer cells; (ii) aumdubin shows high affinity for mitochondrial DUB USP30; (iii) aumdubin induces apoptosis by increasing the ubiquitination and mitochondrial location of Bax protein; and (iv) USP30 inhibition may contribute to Bax-dependent apoptosis induced by aumdubin in lung cancer cells. These results suggest that gold(I)-containing agent aumdubin induces Bax-dependent apoptosis partly through inhibiting the mitochondrial DUB USP30, which could open new avenues for lung cancer therapy.

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A novel resveratrol derivative induces mitotic arrest, centrosome fragmentation and cancer cell death by inhibiting γ-tubulin

Cell Division ◽

10.1186/s13008-019-0046-8 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 3

Author(s):

Gianandrea Traversi ◽

David Sasah Staid ◽

Mario Fiore ◽

Zulema Percario ◽

Daniela Trisciuoglio ◽

...

Keyword(s):

Cell Death ◽

Cancer Cell ◽

Mitotic Arrest ◽

Cancer Cell Death ◽

Resveratrol Derivative

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Natural forms of vitamin E and metabolites—regulation of cancer cell death and underlying mechanisms

IUBMB Life ◽

10.1002/iub.1978 ◽

2018 ◽

Cited By ~ 10

Author(s):

Qing Jiang

Keyword(s):

Cell Death ◽

Vitamin E ◽

Cancer Cell ◽

Cancer Cell Death ◽

Natural Forms ◽

Underlying Mechanisms

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FBXO45-MYCBP2 regulates mitotic cell fate by targeting FBXW7 for degradation

10.1101/493791 ◽

2018 ◽

Author(s):

Kai T. Richter ◽

Yvonne T. Kschonsak ◽

Barbara Vodicska ◽

Ingrid Hoffmann

Keyword(s):

Cell Death ◽

Cell Fate ◽

Chemotherapy Resistance ◽

Mitotic Cell ◽

Mitotic Arrest ◽

Protein Levels ◽

Mitotic Slippage ◽

Microtubule Targeting Agents ◽

Fate Decision ◽

F Box Protein

SUMMARYCell fate decision upon prolonged mitotic arrest induced by microtubule targeting agents depends on the activity of the tumor suppressor and F-box protein FBXW7. FBXW7 promotes mitotic cell death and prevents premature escape from mitosis through mitotic slippage. Mitotic slippage is a process that can cause chemoresistance and tumor relapse. Therefore, understanding the mechanisms that regulate the balance between mitotic cell death and mitotic slippage is an important task. Here we report that FBXW7 protein levels markedly decline during extended mitotic arrest. FBXO45 binds to a conserved acidic N-terminal motif of FBXW7 specifically under a prolonged delay in mitosis, leading to ubiquitylation and subsequent proteasomal degradation of FBXW7 by the FBXO45-MYCBP2 E3 ubiquitin ligase. Moreover, we find that FBXO45-MYCBP2 counteracts FBXW7 in that it promotes mitotic slippage and prevents cell death in mitosis. Targeting this interaction represents a promising strategy to prevent chemotherapy resistance.

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Activity-based protein profiling reveals GSTO1 as the covalent target of piperlongumine and a promising target for combination therapy for cancer

Chemical Communications ◽

10.1039/c9cc00917e ◽

2019 ◽

Vol 55 (30) ◽

pp. 4407-4410 ◽

Cited By ~ 6

Author(s):

Li Li ◽

Yue Zhao ◽

Ran Cao ◽

Lin Li ◽

Gaihong Cai ◽

...

Keyword(s):

Cell Death ◽

Combination Therapy ◽

Synergistic Effect ◽

Cancer Cell ◽

Broad Spectrum ◽

Protein Profiling ◽

Cancer Cell Death ◽

Promising Target ◽

Anti Cancer

Through ABPP, piperlongumine was identified to induce cancer cell death by covalently binding and inhibiting GSTO1 and has a broad spectrum synergistic effect with other anti-cancer agents.

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