Mitosis and Drug Discovery
Marko Kallio, Ph.D.
Senior Specialist and
K. Albin Johansson Senior Cancer Researcher
Turku Centre for Biotechnology
P.O. Box 123, BioCity
(Street adr. Tykistökatu 6 B)
FIN-20521 Turku, Finland or
Dept. Physiology, Inst. Biomedicine, Univ. Turku
Kiinamyllynkatu 10, Medisiina B625
FIN-20520 Turku, Finland
+358-2-333 7578 (Marko Kallio)
+358-2-333 7212 (Dept office)
Description of the Research
Research Focus: Spindle Checkpoint and Chromosome Instability
The Mitosis and Drug Discovery Team investigates mechanisms of cell division in somatic cells and in meiotic systems. Understanding cell division errors may help to explain origin of genomic instability and is expected to identify novel therapeutic possibilities for treatment of cancer.
We are performing high-throughput screens for small molecules, siRNAs and microRNAs with anti-mitotic activity, and especially aiming to identify conditions that suppress cell viability as a consequence of premature inactivation of the spindle assembly checkpoint (SAC), a conserved signaling pathway monitoring the fidelity of mitosis. Moreover, we are investigating the mechanisms of acquired drug resistance, a growing clinical problem in the treatment of cancer. Developed resistance to microtubule drugs has links to malfunction of tubulin and SAC proteins but these mechanisms are poorly understood.
Errors during cell division can result in unequal distribution of DNA between the daughter cells. Gain or loss of chromosomes (aneuploidy) is a known cause for miscarriages and birth defects in human, and a hallmark of cancer. We aim to understand better how defective SAC signaling induces genomic imbalance and thereby contributes to cancer initiation and metastasis. Although the main principles of the SAC function are well documented many molecular details remain to be elucidated. In our current projects, we are focusing on identification and characterization of novel small molecule weight compounds and microRNAs that perturb normal mitotic cell signaling. In our studies, we use various cell-based and biochemical assays as well as versatile cell imaging methods. Moreover, we co-operate with clinical and bio-informatics experts to learn how our molecular discoveries affect tumor cells’ viability and drug response in cancer patients. Our ultimate goal is to develop new lead compounds for pharmaceutical industry and gain molecular level information that can assist in cancer subtyping and/or in predicting tumor cells’ sensitivity to chemotherapy.
1. We aim at discovery and characterization of novel SAC regulating microRNAs and study how their altered expression affects genomic stability and drug response, especially in context of ovarian and breast cancer.
2. We also investigate the function of Ndc80 protein complex that locates at the interface between microtubules and outer kinetochore. We aim at developing novel LMW inhibitors against one of the complex sub-unit, the Hec1 protein.
Our data shows that altered expression of SAC-targeting microRNAs result in mitotic errors, cellular senescence and resistance to microtubule drugs, and thereby contribute to growth potency and chemotherapy sensitivity of individual cancer cells in the tumor tissue. We propose that profiling of specific microRNAs and their target gene expression levels in tumors can have diagnostic value in cancer subtyping and in predicting the therapeutic efficacy of microtubule drugs such as paclitaxel.
Moreover, discovery and preclinical testing of novel LMW compounds with strong anti-cancer activity is expected to fuel hit-to-lead process and advance the drug development.
The Academy of Finland, the Finnish Cancer Institute, the Finnish Cultural Foundation and local graduate schools.
Tambe M, Pruikkonen S, Mäki-Jouppila J, Chen P, Elgaaen BV, Straume AH, Huhtinen K, Cárpen O, Lønning PE, Davidson B, Hautaniemi S and Kallio MJ. (2016) Novel Mad2-targeting miR-493-3p controls mitotic fidelity and cancer cells’ sensitivity to paclitaxel. Oncotarget, 7:12267-85.
Mäki-Jouppila J, Pruikkonen S, Tambe M, Aure MR, Halonen T, Salmela A-L, Laine L, Børresen-Dale A-L, Kallio MJ. (2015) MicroRNA let-7b regulates genomic balance by targeting Aurora B kinase. Mol Oncol, 9:1056-70.
Winsel S, Mäki-Jouppila J, Tambe M, Aure MR, Pruikkonen S, Salmela AL, Halonen T, Leivonen SK, Kallio L, Børresen-Dale AL, Kallio MJ. (2014) Excess of miRNA-378a-5p perturbs mitotic fidelity and correlates with breast cancer tumourigenesis in vivo. Br J Cancer, 111:2142-51.
Mäki-Jouppila JH, Laine LJ, Rehnberg J, Narvi E, Tiikkainen P, Hukasova E, Halonen P, Lindqvist A, Kallio L, Poso A, Kallio MJ. (2014) Centmitor-1, a novel acridinyl-acetohydrazide, possesses similar molecular interaction field and antimitotic cellular phenotype as rigosertib, on 01910.Na. Mol Cancer Ther, 13; 1054-1066.
Narvi E, Jaakkola K, Winsel S, Oetken-Lindholm C, Halonen P, Kallio L and Kallio MJ. (2013) Altered TUBB3 expression contributes to the epothilone response of mitotic cells. British J. Cancer, 108, 82-90.
Salmela AL, Pouwels J, Waris S, Laine L, Mäki-Jouppila J, Kohonen P, Kallio L, Toivonen P, Kallio L and Kallio M. (2013) Novel pyrimidine-2,4-diamine derivative suppresses the spindle assembly checkpoint activity by targeting aurora B kinase. Carcinogenesis, 34, 436-45.