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Mitotic checkpoint defects: en route to cancer and drug resistance

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Abstract

Loss of mitosis regulation is a common feature of malignant cells that leads to aberrant cell division with inaccurate chromosome segregation. The mitotic checkpoint is responsible for faithful transmission of genetic material to the progeny. Defects in this checkpoint, such as mutations and changes in gene expression, lead to abnormal chromosome content or aneuploidy that may facilitate cancer development. Furthermore, a defective checkpoint response is indicated in the development of drug resistance to microtubule poisons that are used in treatment of various blood and solid cancers for several decades. Mitotic slippage and senescence are important cell fates that occur even with an active mitotic checkpoint and are held responsible for the resistance. However, contradictory findings in both the scenarios of carcinogenesis and drug resistance have aroused questions on whether mitotic checkpoint defects are truly responsible for these dismal outcomes. Here, we discuss the possible contribution of the faulty checkpoint signaling in cancer development and drug resistance, followed by the latest research on this pathway for better outcomes in cancer treatment.

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Abbreviations

MC:

Mitotic checkpoint

SAC:

Spindle assembly checkpoint

MCC:

Mitotic checkpoint complex

APC/C:

Anaphase-promoting complex/cyclosome

MAD:

Mitotic arrest deficiency protein

BUB:

Budding uninhibited by benzimidazole

BUBR1:

Budding uninhibited by benzimidazole-related 1

CIN:

Chromosomal instabiliy

MTA:

Microtubule targeting agents

CDC20:

Cell division control protein 20

CycB-Cdk1:

Cyclin B and CDk1 complex

AOM:

Azoxymethane

DMBA:

7,12-Dimethylbenz[a]anthracene

ER-beta:

Estrogen receptor-beta

RZZ:

Rod-Zw10-Zwilch

KMN:

Knl1-Mis12-Ndc80 complex

MPS1:

Monopolar spindle protein 1

SASP:

Senescence-associated secretory phenotype

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Acknowledgments

This work was supported by a grant (R.12014/12/2018-HR) from the Department of Health Research, Govt. of India under Young Scientist-Human Resources Development (HRD) Scheme, to S.S.

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Authors and Affiliations

  1. Department of Pathology and Cancer Screening, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700026, India

    Sinjini Sarkar, Pranab Kumar Sahoo, Sutapa Mahata, Ranita Pal, Dipanwita Ghosh, Tanuma Mistry, Sushmita Ghosh & Vilas D. Nasare

  2. Department of Pharmaceutical Technology, Jadavpur University, Kolkata, West Bengal, 700032, India

    Sinjini Sarkar & Tanmoy Bera

Authors
  1. Sinjini Sarkar
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  2. Pranab Kumar Sahoo
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  3. Sutapa Mahata
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  4. Ranita Pal
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  5. Dipanwita Ghosh
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  6. Tanuma Mistry
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  8. Tanmoy Bera
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  9. Vilas D. Nasare
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Contributions

SS and VDN conceptualized and wrote the main manuscript, and all the authors contributed in re-writing and editing the final manuscript. All authors read and approved the final manuscript.

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Correspondence to Vilas D. Nasare.

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Sarkar, S., Sahoo, P.K., Mahata, S. et al. Mitotic checkpoint defects: en route to cancer and drug resistance. Chromosome Res 29, 131–144 (2021). https://doi.org/10.1007/s10577-020-09646-x

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  • DOI: https://doi.org/10.1007/s10577-020-09646-x

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