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Role of Kinesin Molecular Motor Proteins in Cancer

Allison A. Curley, Ph.D.

Kinesin superfamily proteins, or KIFs, are microtubule-dependent molecular motors whose movement is critical to a variety of cellular processes including mitosis, meiosis, and axonal transport. So far, 45 KIF genes grouped into 15 families have been identified, and at least twice as many proteins are thought to exist due to alternative splicing1. KIFs transport cargo along microtubules much like a train moves along a rail, using the energy generated from the hydrolysis of ATP to drive conformational changes that produce motility2.

Given the critical role of KIFs in mitosis, and the fact that tumor growth is characterized by out-of-control mitosis, it is perhaps not surprising that KIFs have been linked to cancer. In fact, members of nearly all KIF families have been implicated in tumor growth, and levels of several KIFs are altered in various cancers3. For example, KIF11 is highly expressed in chronic myeloid leukemia4, and its overexpression leads to tumor growth in mice5. In addition, KIF4A is overexpressed in cervical cancer6, and has been identified as a potential prognostic biomarker for lung cancer7.

Inhibitors of two KIFs are currently being tested in cancer clinical trials – KIF10 (or CENP-E) and KIF11 (also known as EGF5) – and over 38 trials have been completed or are currently ongoing8. The KIF10 inhibitor GSK923295, which induces cell cycle arrest and subsequent cell death, has showed promise in preclinical studies, as well as in a phase I trial that examined the drug's safety and tolerability9,10. At least six KIF11-targeting drugs are currently under evaluation for the treatment multiple cancers, including prostate, breast, and renal cancer as well as leukemia8. Although KIF10 and KIF11 inhibitors have been the best studied to date, several other KIFs are also potential anticancer targets with therapeutics under development.

Bethyl’s KIF antibodies include the following:


Detection of human KIF14 (orange) in formaldehyde-fixed HeLa cells by ICC-IF.

Antibody: Rabbit anti-KIF14 (IHC-00475). Secondary: DyLight® 550-conjugated goat anti-rabbit IgG (A120-201D3). Counterstain: Wheat Germ Agglutinin, Phalloidin Alexa Fluor® 488-conjugated (green) and DAPI (blue).

Detection of human EG5/KIF11 by WB of immunoprecipitates from 293T lysate.

Detection of human EG5/KIF11 by WB of immunoprecipitates from 293T lysate. Antibodies: Rabbit anti-EG5/KIF11 (A301-076A & A301-075A). Secondary: ReliaBLOT® reagents (WB120).

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References

1. Miki H, Setou M, Kaneshiro K, Hirokawa N. 2001. All kinesin superfamily protein, KIF, genes in mouse and human. Proc Natl Acad Sci USA. Jun 19;98(13):7004-7011.

2. Hirokawa N, Noda Y, Tanaka Y, Niwa S. 2009. Kinesin superfamily motor proteins and intracellular transport. Nat Rev Mol Cell Biol. Oct;10(10):682-696.

3. Yu Y, Feng YM. 2010. The role of kinesin family proteins in tumorigenesis and progression: Potential biomarkers and molecular targets for cancer therapy. Cancer. Nov 15;116(22):5150-5160.

4. Carter BZ, Mak DH, Shi Y, Schober WD, Wang RY, Konopleva M, Koller E, Dean NM, Andreef M. 2006. Regulation and targeting of eg5, a mitotic motor protein in blast crisis CML: Overcoming imatinib resistance. Cell Cycle. Oct;5(19):2223-2229.

5. Castillo A, Morse HC, Godfrey VL, Naeem R, Justice MJ. 200. Overexpression of eg5 causes genomic instability and tumor formation in mice. Cancer Res. Nov 1;67(21):10138-10147.

6. Narayan G, Bourdon V, Chaganti S, Arias-Pulido H, Nandula SV, Rao PH, Gissmann L, Dürst M, Schneider A, Pothuri B, et al. 2007. Gene dosage alterations revealed by cdna microarray analysis in cervical cancer: Identification of candidate amplified and overexpressed genes. Genes Chromosomes Cancer. Apr;46(4):373-384.

7. Taniwaki M, Takano A, Ishikawa N, Yasui W, Inai K, Nishimura H, Tsuchiya E, Kohno N, Nakamura Y, Daigo Y. 2007. Activation of KIF4A as a prognostic biomarker and therapeutic target for lung cancer. Clin Cancer Res. Nov 15;13(22 Pt 1):6624-6631.

8. Rath O, Kozielski F. 2012. Kinesins and cancer. Nat Rev Cancer. Jul 24;12(8):527-539.

9. Lock RB, Carol H, Morton CL, Keir ST, Reynolds CP, Kang MH, et al. 2012. Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program. Pediatr Blood Cancer. Jun;58(6):916-923.

10. Chung V, Heath EI, Schelman WR, Johnson BM, Kirby LC, Lynch KM, Botbyl JD, Lampkin TA, Holen KD. 2012. First-time-in-human study of GSK923295, a novel antimitotic inhibitor of centromere-associated protein E (CENP-E), in patients with refractory cancer. Cancer Chemother Pharmacol. Mar;69(3):733-741.