Interview with Dr. Anutosh Ganguly from the University of Texas Medical School
Oncotarget | Interview with Dr. Anutosh Ganguly from the Department of Integrative Biology and Pharmacology, University of Texas Medical School, 6431 Fannin St., Houston, Texas 77030, USA talking about their research published in Volume 2 Issue 5 titled "Class III β-Tubulin Counteracts the Ability of Paclitaxel to Inhibit Cell Migration"
Oncotarget published "Class III β-Tubulin Counteracts the Ability of Paclitaxel to Inhibit Cell Migration" which reported that To elucidate its action, we tested β3's effect on cell migration.
Expression of β3 in HeLa and MCF-7 did not alter the intrinsic rate of cell migration, but it prevented the inhibition of migration by low, nontoxic concentrations of paclitaxel.
The effects on cell motility were confirmed in CHO cells with tetracycline regulated expression of β3. Cell migration and microtubule dynamics were inhibited by similar concentrations of paclitaxel, but required a 5-10 fold higher drug concentration when β3 was expressed.
The directionality of migration was normal in paclitaxel, but cells spent more time in a “paused” state during which there was no net movement.
These studies support a model in which paclitaxel inhibits cell migration by suppressing microtubule dynamics and β3-tubulin counteracts paclitaxel action by maintaining microtubule dynamic activity.
Dr. Fernando Cabral from The University of Texas Medical School said, "Microtubules form an important cytoskeletal network involved in cell shape, vesicle transport, cell motility, chromosome segregation, and cell division."
"Microtubules form an important cytoskeletal network involved in cell shape, vesicle transport, cell motility, chromosome segregation, and cell division."
Studies in cultured mammalian cells showed that cellular microtubules incorporate all available β-tubulin isotypes including ectopic and chimeric proteins with little or no change to the microtubule network.
In contrast, overexpression of the more divergent β5 and β6 isotypes produces dramatic effects on cell division, microtubule assembly, and cellular responses to drugs that target the microtubule cytoskeleton.
Although β3 is normally restricted to neuronal and Sertoli cells, it has been found to be inappropriately expressed in tumor cells from diverse tissues and its presence appears to correlate with tumor aggressiveness and resistance to therapy.
As a measure of tumor cell aggressiveness, we tested the effects of β3 expression on the ability of paclitaxel to inhibit cell migration.
Figure 6: Calculation of cell movement parameters. Microtubule tracks similar to those in Figure 5 were used to measure cell velocity (using only intervals during which the cells actually moved, solid bars), cell migration (1/2 the rate at which the wound closed, open bars), and frequency of pauses (number of intervals/h in which there was no cell movement, shaded bars).
The Cabral Research Team concluded in their Oncotarget Research Output that arguing in favor of a direct role of β3 in tumor cell behavior, a number of studies have reported that cells selected for resistance to the cytotoxic effects of paclitaxel have increased expression of β3, suggesting that this isotype can confer resistance to the drug.
Subsequent studies in this laboratory confirmed this idea but demonstrated that increased β3 expression alone can only confer very weak 1.5-fold resistance and that it acts by altering the extent of microtubule assembly.
In contrast to the weak effects on the cytotoxic action of the drug, we show here that β3 expression produces a 10-fold resistance to the ability of paclitaxel to inhibit cell migration.
Because cell migration is a critical step in angiogenesis and tumor cell metastasis, our data suggest that β3's effects on motility are a better explanation for the observation that its expression correlates with poor prognosis.
DOI - https://doi.org/10.18632/oncotarget.250
Full text - https://www.oncotarget.com/article/250/text/
Correspondence to - Fernando Cabral - [email protected]
Keywords - tubulin isotypes, microtubules, dynamic instability, motility, drug resistance
