1. Regulation of microtubule dynamics by DIAPH3 influences amoeboid tumor cell mechanics and sensitivity to taxanes
- Author
-
Martin H. Hager, Jiyoung Choi, Dolores Di Vizio, Rosalyn M. Adam, Wei Yang, Sungyong You, Sara Pollan, Jayoung Kim, Kavitha Rajendran, Kenneth Steadman, Cristiana Spinelli, Arkadiusz Gertych, Samantha Morley, Ramaswamy Krishnan, Michael R. Freeman, Beatrice S. Knudsen, and Bo Zhou
- Subjects
Male ,medicine.medical_specialty ,Formins ,Breast Neoplasms ,Biology ,Microtubules ,Article ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Downregulation and upregulation ,Microtubule ,Prostate ,Internal medicine ,medicine ,Gene silencing ,Cytotoxic T cell ,Humans ,Gene Silencing ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,0303 health sciences ,Multidisciplinary ,Taxane ,Prostatic Neoplasms ,medicine.disease ,3. Good health ,Endocrinology ,medicine.anatomical_structure ,Cell culture ,Epothilones ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Taxoids - Abstract
Taxanes are widely employed chemotherapies for patients with metastatic prostate and breast cancer. Here, we show that loss of Diaphanous-related formin-3 (DIAPH3), frequently associated with metastatic breast and prostate cancers, correlates with increased sensitivity to taxanes. DIAPH3 interacted with microtubules (MT) and its loss altered several parameters of MT dynamics as well as decreased polarized force generation, contractility and response to substrate stiffness. Silencing of DIAPH3 increased the cytotoxic response to taxanes in prostate and breast cancer cell lines. Analysis of drug activity for tubulin-targeted agents in the NCI-60 cell line panel revealed a uniform positive correlation between reduced DIAPH3 expression and drug sensitivity. Low DIAPH3 expression correlated with improved relapse-free survival in breast cancer patients treated with chemotherapeutic regimens containing taxanes. Our results suggest that inhibition of MT stability arising from DIAPH3 downregulation enhances susceptibility to MT poisons and that the DIAPH3 network potentially reports taxane sensitivity in human tumors.
- Published
- 2015