Interphase microtubules: chief casualties in the war on cancer?

Abstract

Microtubule-targeting agents (MTAs) profoundly affect interphase cells, such as by disrupting axonal transport, transcription, translation, mitochondrial permeability, immune cell function, directional migration and centrosome clustering. This finding is antithetical to the conventionally held notion that MTAs act on mitosis to trigger arrest-mediated apoptotic cell death. Furthermore, the paucity of mitotic cells in patient tumors and lack of correlation of MTA efficacy with tumor proliferation rate provide strong impetus to re-examine the mechanistic basis of action of MTAs, with an eye toward interphase activities. Whereas targeted antimitotics have unequivocally failed their promise across clinical studies, MTAs constitute a mainstay of chemotherapy. This paradox necessitates the conclusion that MTAs exert mitosis-independent effects, spurring a dramatic paradigm shift in our understanding of the mode of action of MTAs.

Figure 1. Diverse anticancer interphase activities of microtubule-targeting agents (MTAs)

(a) _[s4]Centrosome clustering is antagonized by novel microtubule-binding agents like griseofulvin and noscapinoids, which could impact diverse cellular activities such as Golgi compaction and polarization along with cell polarization and directional migration. (b) MTAs are mitotoxic and induce voltage-dependent anion channel opening with release of Ca²⁺ and cytochrome c. (c) MTAs also disrupt delivery of mRNA along interphase microtubule tracks to polysomes and (d) induce mRNA release from polysomes. (e) MTAs improve MHC class I expression by cancer cells, which could render them more ‘perceptible’ to the immune system, along with increasing activation of (f) dendritic cells, (g) cytotoxic T lymphocytes and (h) macrophages, among other generally proinflammatory, antitumor leukocytes. (i) By impeding vesicular traffic to the cell front, MTAs can inhibit the delivery of vesicles containing actin- and focal-adhesion-regulating factors, and matrix-digesting proteases, which normally promote leading edge protrusion and stromal invasion, respectively. (j) Similarly, interphase microtubule tracks are required for timely endocytosis of focal adhesion components from the leading edge and recycling to the trailing edge to propel directional migration. (k) Finally, MTAs interfere with transcription factor transport by motors to the nucleus with (l) up- or down-regulation of tumor suppressor or oncogenes, respectively. Abbreviations: MHC, major histocompatibility complex; VDAC, voltage-dependent anion channel.

Figure 1. Diverse anticancer interphase activities of microtubule-targeting agents (MTAs)

(a) _[s4]Centrosome clustering is antagonized by novel microtubule-binding agents like griseofulvin and noscapinoids, which could impact diverse cellular activities such as Golgi compaction and polarization along with cell polarization and directional migration. (b) MTAs are mitotoxic and induce voltage-dependent anion channel opening with release of Ca²⁺ and cytochrome c. (c) MTAs also disrupt delivery of mRNA along interphase microtubule tracks to polysomes and (d) induce mRNA release from polysomes. (e) MTAs improve MHC class I expression by cancer cells, which could render them more ‘perceptible’ to the immune system, along with increasing activation of (f) dendritic cells, (g) cytotoxic T lymphocytes and (h) macrophages, among other generally proinflammatory, antitumor leukocytes. (i) By impeding vesicular traffic to the cell front, MTAs can inhibit the delivery of vesicles containing actin- and focal-adhesion-regulating factors, and matrix-digesting proteases, which normally promote leading edge protrusion and stromal invasion, respectively. (j) Similarly, interphase microtubule tracks are required for timely endocytosis of focal adhesion components from the leading edge and recycling to the trailing edge to propel directional migration. (k) Finally, MTAs interfere with transcription factor transport by motors to the nucleus with (l) up- or down-regulation of tumor suppressor or oncogenes, respectively. Abbreviations: MHC, major histocompatibility complex; VDAC, voltage-dependent anion channel.