Editing Spindle checkpoint (section)

== Spindle checkpoint defects and cancer ==
When the spindle checkpoint misfunctions, this can lead to chromosome missegregation, [[aneuploidy]] and even [[tumorigenesis]].<ref name="Nature"/> Transformation occurs and is accelerated when maintenance of genomic integrity breaks down especially at the gross level of whole chromosomes or large portions of them. In fact, aneuploidy is the most common characteristic of human solid tumors and thus the spindle assembly checkpoint might be regarded as a possible target for anti-tumour therapy.<ref name="Kops2005">{{cite journal | vauthors = Kops GJ, Weaver BA, Cleveland DW | title = On the road to cancer: aneuploidy and the mitotic checkpoint | journal = Nature Reviews. Cancer | volume = 5 | issue = 10 | pages = 773–85 | date = October 2005 | pmid = 16195750 | doi = 10.1038/nrc1714 | s2cid = 2515388 }}</ref> This is a much underappreciated fact since mutations in specific genes known as [[oncogenes]] or [[tumor suppressor]] are primarily thought to be behind genetic instability and tumorigenesis. Usually the various checkpoints in the cell cycle take care of genomic integrity via highly conserved redundant mechanisms that are important for maintaining cellular homeostasis and preventing tumorigenesis. Several spindle assembly checkpoint proteins act both as positive and negative regulators to ensure the proper chromosome segregation in each cell cycle preventing chromosome instability (CIN) also known as [[genome instability]]. [[Image:Histogram from cytometry - aneuploidy.PNG|thumb|right|Cytometric analysis of malignant carcinoma displaying aneuploidy]]Genomic integrity is now appreciated at several levels where some tumors display instability manifested as base substitutions, insertions, and deletions, while the majority displays gains or losses of whole chromosomes.<ref name="Lengauer1998">{{cite journal | vauthors = Lengauer C, Kinzler KW, Vogelstein B | title = Genetic instabilities in human cancers | journal = Nature | volume = 396 | issue = 6712 | pages = 643–9 | date = December 1998 | pmid = 9872311 | doi = 10.1038/25292 | bibcode = 1998Natur.396..643L | s2cid = 204996480 }}</ref>

Due to the fact that alterations in mitotic regulatory proteins can lead to aneuploidy and this is a frequent event in [[cancer]],<ref name="weaver2006">{{cite journal | vauthors = Weaver BA, Cleveland DW | title = Does aneuploidy cause cancer? | journal = Current Opinion in Cell Biology | volume = 18 | issue = 6 | pages = 658–67 | date = December 2006 | pmid = 17046232 | doi = 10.1016/j.ceb.2006.10.002 }}</ref> it was initially thought that these genes could be mutated in cancerous tissues.<ref name="Cahill1998">{{cite journal | vauthors = Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B | title = Mutations of mitotic checkpoint genes in human cancers | journal = Nature | volume = 392 | issue = 6673 | pages = 300–3 | date = March 1998 | pmid = 9521327 | doi = 10.1038/32688 | bibcode = 1998Natur.392..300C | s2cid = 4416376 }}</ref>

=== Mutated genes in cancers ===

In some cancers the genes that underlie the defects resulting in transformation are well characterized. In the hematological cancers such as multiple myeloma cytogenetic abnormalities are very common due to the inherent nature of DNA breaks needed for immunoglobulin gene rearrangement. However, defects in proteins such as MAD2 that function predominantly at the SAC also are characterized in multiple myeloma.<ref name="Diaz Rodriguez">{{cite journal | vauthors = Díaz-Rodríguez E, Álvarez-Fernández S, Chen X, Paiva B, López-Pérez R, García-Hernández JL, San Miguel JF, Pandiella A | title = Deficient spindle assembly checkpoint in multiple myeloma | journal = PLOS ONE | volume = 6 | issue = 11 | pages = e27583 | year = 2011 | pmid = 22132115 | pmc = 3223182 | doi = 10.1371/journal.pone.0027583 | bibcode = 2011PLoSO...627583D | doi-access = free }} {{open access}}</ref> Most solid tumors are also predominantly aneuploid. For colorectal cancer,  BUB1 and BUBR1 and amplification of STK15 are key regulators that have been implicated in the genomic instability resulting in cancer.<ref name="Grady2004">{{cite journal |doi= 10.1023/A:1025861527711|year=2004 |last1=Grady |first1= William M. |journal=Cancer and Metastasis Reviews|volume=23 |issue= 1–2 |pages= 11–27|title= Genomic instability and colon cancer|pmid=15000146 |s2cid=1177511 }}</ref>  In breast cancer, the genetic form characterized by the BRCA-1 gene exhibits greater levels of genomic instability than sporadic forms. Experiments showed that BRCA-1 null mice have decreased expression of the key spindle checkpoint protein MAD2 .<ref name="Wang2004">{{cite journal | vauthors = Wang RH, Yu H, Deng CX | title = A requirement for breast-cancer-associated gene 1 (BRCA1) in the spindle checkpoint | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 49 | pages = 17108–13 | date = December 2004 | pmid = 15563594 | pmc = 535394 | doi = 10.1073/pnas.0407585101 | bibcode = 2004PNAS..10117108W | doi-access = free }}</ref> For other cancers, more work is warranted to identify the causes of aneuploidy.

=== Other genes not traditionally associated with the SAC in cancer ===

Clearly variations in the physiological levels of these proteins (such as Mad2 or BubR1) are associated with aneuploidy and tumorigenesis, and this has been demonstrated using  [[animal model]]s.<ref name="Sotillo2007">{{cite journal | vauthors = Sotillo R, Hernando E, Díaz-Rodríguez E, Teruya-Feldstein J, Cordón-Cardo C, Lowe SW, Benezra R | title = Mad2 overexpression promotes aneuploidy and tumorigenesis in mice | journal = Cancer Cell | volume = 11 | issue = 1 | pages = 9–23 | date = January 2007 | pmid = 17189715 | pmc = 1850996 | doi = 10.1016/j.ccr.2006.10.019 }}</ref><ref name="yamamoto2007">{{cite journal | vauthors = Yamamoto Y, Matsuyama H, Chochi Y, Okuda M, Kawauchi S, Inoue R, Furuya T, Oga A, Naito K, Sasaki K | title = Overexpression of BUBR1 is associated with chromosomal instability in bladder cancer | journal = Cancer Genetics and Cytogenetics | volume = 174 | issue = 1 | pages = 42–7 | date = April 2007 | pmid = 17350465 | doi = 10.1016/j.cancergencyto.2006.11.012 }}</ref> However, recent studies indicate that what seems to happen is a more complicated scenario: aneuploidy would drive a high incidence of tumorigenesis only when alterations in the levels of specific mitotic checkpoint components (either reduction or overexpression) in tissues is also inducing other defects able to predispose them to tumors.<ref name="weaver2009">{{cite journal | vauthors = Weaver BA, Cleveland DW | title = The role of aneuploidy in promoting and suppressing tumors | journal = The Journal of Cell Biology | volume = 185 | issue = 6 | pages = 935–7 | date = June 2009 | pmid = 19528293 | pmc = 2711620 | doi = 10.1083/jcb.200905098 }}</ref>
That is, defects such as an increase in DNA damage, chromosomal rearrangements, and/or a decreased incidence of cell death. For some mitotic checkpoint components, it is known that they are implicated in functions outside mitosis: nuclear import (Mad1), transcriptional repression (Bub3), and cell death, DNA damage response, aging, and [[megakaryopoiesis]] for BubR1. All this supports the conclusion that increase in tumorigenesis is associated with defects other than aneuploidy alone.<ref name="weaver2009"/>

Cancer-associated mutations affecting known checkpoint genes like BUB1 or BUBR1 are actually rare. However, several proteins implicated in cancer have intersections to spindle assembly networks. Key tumor suppressors such as [[p53]] also play a role in the spindle checkpoint. Absence of p53, the most commonly mutated gene in human cancer, has a major effect on cell cycle checkpoint regulators and has been shown to act at the G1 checkpoint in the past, but now appears to be important in regulating the spindle checkpoint as well.<ref name="Cross1995">{{cite journal |doi= 10.1126/science.7871434|year=1995 |last1=Cross |first1= Shawn M. | last2=Sanchez |first2=Carissa A| last3=Morgan |first3= Catherine A. |last4=Schimke |first4= Melana K. |last5=Reid|first5= Brian J.| journal=Science|volume=3 |issue= 5202 |pages= 1353–1356|title= A p53-dependant mouse spindle checkpoint|pmid=7871434 |bibcode=1995Sci...267.1353C |s2cid=38128370 }}</ref>  Another key aspect of cancer is inhibition of cell death or [[apoptosis]]. [[Survivin]], a member of the inhibitor of apoptosis (IAP) family, is localized in pools at microtubules of the mitotic spindle near the centrosomes and at the kinetochores of metaphase chromosomes. Not only does survivin inhibit apoptosis to promote tumorigenesis, but it has been implicated (through experimental knockout mice) as an important regulator of chromosome segregation, and late stage mitosis similar to its role in more primitive organisms.<ref name="Altieri2001">{{cite journal | vauthors = Altieri DC | title = The molecular basis and potential role of survivin in cancer diagnosis and therapy | journal = Trends in Molecular Medicine | volume = 7 | issue = 12 | pages = 542–7 | date = December 2001 | pmid = 11733216 | doi = 10.1016/S1471-4914(01)02243-2 }}</ref>

Other aspects of the spindle assembly checkpoint such as kinetochore attachment, microtubule function, and sister chromatid cohesion are likely to be defective as well to cause aneuploidy. Cancer cells have been observed to divide in multiple directions by evading the spindle assembly checkpoint resulting in multipolar mitoses.<ref name="Gisselsson2008">{{cite journal | vauthors = Gisselsson D, Håkanson U, Stoller P, Marti D, Jin Y, Rosengren AH, Stewénius Y, Kahl F, Panagopoulos I | title = When the genome plays dice: circumvention of the spindle assembly checkpoint and near-random chromosome segregation in multipolar cancer cell mitoses | journal = PLOS ONE | volume = 3 | issue = 4 | pages = e1871 | date = April 2008 | pmid = 18392149 | pmc = 2289843 | doi = 10.1371/journal.pone.0001871 | bibcode = 2008PLoSO...3.1871G | doi-access = free }} {{open access}}</ref> The multipolar metaphase-anaphase transition occurs through an incomplete separase cycle that results in frequent nondisjunction events which amplify aneuploidy in cancer cells.

=== SAC cancer therapies ===
[[Image:taxol.svg|thumb|right|The chemical structure of paclitaxel or TAXOL, a mitotic inhibitor used in cancer chemotherapy]]
Advances in this field have led to the introduction of development of some therapies targeted at spindle assembly defects. Older treatments such as vinca alkaloids and taxanes target microtubules that accompany mitotic spindle formation via disruption of microtubule dynamics which engage the SAC arresting the cell and eventually leading to its death.<ref name="Zhou2005">{{cite journal | vauthors = Zhou J, Giannakakou P | title = Targeting microtubules for cancer chemotherapy | journal = Current Medicinal Chemistry. Anti-Cancer Agents | volume = 5 | issue = 1 | pages = 65–71 | date = January 2005 | pmid = 15720262 | doi = 10.2174/1568011053352569 }}</ref> [[Taxol]] and [[Docetaxel]], which can induce [[mitotic catastrophe]], both are still used in the treatment of breast cancer, ovarian cancer and other types of epithelial cancer.<ref>{{Cite journal |last1=Denisenko |first1=Tatiana V. |last2=Sorokina |first2=Irina V. |last3=Gogvadze |first3=Vladimir |last4=Zhivotovsky |first4=Boris |date=2016-01-01 |title=Mitotic catastrophe and cancer drug resistance: A link that must to be broken |url=https://www.sciencedirect.com/science/article/pii/S1368764615000564 |journal=Drug Resistance Updates |language=en |volume=24 |pages=1–12 |doi=10.1016/j.drup.2015.11.002 |pmid=26830311 |issn=1368-7646|url-access=subscription }}</ref> However, these treatments are often characterized by high rates of side effects and drug resistance.

Other targets within the network of regulators that influence the SAC are also being pursued; strong interest has shifted towards the [[aurora kinase]] proteins.<ref name="Carvajal 2006">{{cite journal | vauthors = Carvajal RD, Tse A, Schwartz GK | title = Aurora kinases: new targets for cancer therapy | journal = Clinical Cancer Research | volume = 12 | issue = 23 | pages = 6869–75 | date = December 2006 | pmid = 17145803 | doi = 10.1158/1078-0432.CCR-06-1405 | doi-access = free }}</ref> The kinase gene [[Aurora A]] when amplified acts as an oncogene overriding the SAC leading to abnormal initiation of anaphase and subsequent aneuploidy and also resistance to TAXOL .<ref name="Anand2003">{{cite journal | vauthors = Anand S, Penrhyn-Lowe S, Venkitaraman AR | title = AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol | journal = Cancer Cell | volume = 3 | issue = 1 | pages = 51–62 | date = January 2003 | pmid = 12559175 | doi = 10.1016/S1535-6108(02)00235-0 | doi-access = free }}</ref> Excitingly, a small molecule inhibitor of Aurora A has shown antitumor effects in an in vivo model suggesting that this might be a good target for further clinical development.<ref name="Harrington2004">{{cite journal | vauthors = Harrington EA, Bebbington D, Moore J, Rasmussen RK, Ajose-Adeogun AO, Nakayama T, Graham JA, Demur C, Hercend T, Diu-Hercend A, Su M, Golec JM, Miller KM | title = VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo | journal = Nature Medicine | volume = 10 | issue = 3 | pages = 262–7 | date = March 2004 | pmid = 14981513 | doi = 10.1038/nm1003 | s2cid = 12918452 }}</ref> [[Aurora B]] inhibitors, which are also in clinical development lead to abnormal kinetochore to microtubule attachment and abrogate the mitotic checkpoint as well.<ref name=" Carvajal 2006"/> Survivin is also an attractive molecular target for clinical therapeutic development as it acts as a major node in a multitude of pathways, one of which is spindle formation and checkpoint control.<ref name="Altieri2008">{{cite journal | vauthors = Altieri DC | title = Survivin, cancer networks and pathway-directed drug discovery | journal = Nature Reviews. Cancer | volume = 8 | issue = 1 | pages = 61–70 | date = January 2008 | pmid = 18075512 | doi = 10.1038/nrc2293 | s2cid = 25597711 }}</ref> Even further approaches have included a look at inhibition of mitotic motor proteins like KSP. These inhibitors, which have recently entered clinical trials, cause mitotic arrest and by engaging the spindle assembly checkpoint and induce apoptosis.<ref name="Tao2005">{{cite journal | vauthors = Tao W, South VJ, Zhang Y, Davide JP, Farrell L, Kohl NE, Sepp-Lorenzino L, Lobell RB | title = Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage | journal = Cancer Cell | volume = 8 | issue = 1 | pages = 49–59 | date = July 2005 | pmid = 16023598 | doi = 10.1016/j.ccr.2005.06.003 | doi-access = free }}</ref><ref name= Sinha2019>{{citation | last1 = Sinha | first1 = D. | last2 = Duijf | first2 = P.H.G. | last3 = Khanna | first3 = K.K. | year = 2019 | title = Mitotic slippage: an old tale with a new twist | journal = Cell Cycle | volume = 18 | issue = 1 | pages = 7–15 | doi = 10.1080/15384101.2018.1559557 | pmid = 30601084| pmc = 6343733 }}</ref>