βIII-tubulin overexpression in cancer: Causes, consequences, and potential therapies

Kanakkanthara, Arun; Miller, John H.

doi:10.1016/j.bbcan.2021.188607

Cited by 28 publications

(26 citation statements)

References 168 publications

(241 reference statements)

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“…Another method to generate drug resistance is the expression of different isotypes of βtubulin to desensitize cells to MTAs [247]. Cancer cells favor the expression of βIII-tubulin, which interferes with the suppression of dynamic instability by taxanes [248][249][250][251]. In fact, inhibiting βIII-tubulin by siRNA renders cells more sensitive to taxanes and triggers cell death by apoptosis [252,253].…”

Section: Mtas and Drug Resistancementioning

confidence: 99%

Microtubule Targeting Agents in Disease: Classic Drugs, Novel Roles

Wordeman

Vicente

2021

Cancers

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Microtubule-targeting agents (MTAs) represent one of the most successful first-line therapies prescribed for cancer treatment. They interfere with microtubule (MT) dynamics by either stabilizing or destabilizing MTs, and in culture, they are believed to kill cells via apoptosis after eliciting mitotic arrest, among other mechanisms. This classical view of MTA therapies persisted for many years. However, the limited success of drugs specifically targeting mitotic proteins, and the slow growing rate of most human tumors forces a reevaluation of the mechanism of action of MTAs. Studies from the last decade suggest that the killing efficiency of MTAs arises from a combination of interphase and mitotic effects. Moreover, MTs have also been implicated in other therapeutically relevant activities, such as decreasing angiogenesis, blocking cell migration, reducing metastasis, and activating innate immunity to promote proinflammatory responses. Two key problems associated with MTA therapy are acquired drug resistance and systemic toxicity. Accordingly, novel and effective MTAs are being designed with an eye toward reducing toxicity without compromising efficacy or promoting resistance. Here, we will review the mechanism of action of MTAs, the signaling pathways they affect, their impact on cancer and other illnesses, and the promising new therapeutic applications of these classic drugs.

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Section: Mtas and Drug Resistancementioning

confidence: 99%

Microtubule Targeting Agents in Disease: Classic Drugs, Novel Roles

Wordeman

Vicente

2021

Cancers

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“…Despite its restricted and predominantly neuronal cell-type distribution in normal tissues, the βIII isotype is expressed in a broad range of human tumors of neuronal and non-neuronal origin. At present, there is a general agreement that abnormal overexpression of βIII-tubulin in non-neuronal cancers is associated with an overall proclivity for aggressive tumor behavior and poor patient outcome [ 32 ].…”

Section: Microtubules As Targets In Cancer Chemotherapymentioning

confidence: 99%

Dysregulation of Microtubule Nucleating Proteins in Cancer Cells

Dráberová

2021

Cancers

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In cells, microtubules typically nucleate from microtubule organizing centers, such as centrosomes. γ-Tubulin, which forms multiprotein complexes, is essential for nucleation. The γ-tubulin ring complex (γ-TuRC) is an efficient microtubule nucleator that requires additional centrosomal proteins for its activation and targeting. Evidence suggests that there is a dysfunction of centrosomal microtubule nucleation in cancer cells. Despite decades of molecular analysis of γ-TuRC and its interacting factors, the mechanisms of microtubule nucleation in normal and cancer cells remains obscure. Here, we review recent work on the high-resolution structure of γ-TuRC, which brings new insight into the mechanism of microtubule nucleation. We discuss the effects of γ-TuRC protein dysregulation on cancer cell behavior and new compounds targeting γ-tubulin. Drugs inhibiting γ-TuRC functions could represent an alternative to microtubule targeting agents in cancer chemotherapy.

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“…But the Kaplan-Meier survival analysis suggested functional cooperation of these two proteins in the aggressiveness of the disease as the high expression of both these proteins or increased expression of even one of these proteins can significantly lead to poor prognosis. It is worthwhile to mention here that, like TUBB4B, its close relatives TUBB2 and TUBB3 have been shown to predict poor survival, the former regulating the cancer energetics through VDAC and the latter by imparting resistance to microtubule targeting agents ( 24 , 38 – 41 ). Our results show that the mechanism by which TUBB4B influences survival is through another means, possibly by regulating the proper localization of Ephrin-B1 in the CSC niche.…”

Section: Discussionmentioning

confidence: 98%

“…βII tubulin is shown to regulate Voltage-Dependent Anion Channels (VDACs) in the mitochondrial outer membrane, which act as a critical regulator of the Warburg effect observed in cancer cells ( 39 , 40 ). At the same time, overexpression of βIII-tubulin (TUBB3) is associated with the development of resistance to microtubule-targeting agents, resistance to apoptosis, and development of metastasis ( 41 ). Also, nuclear localization of βII tubulin is associated with poor outcomes in cancers ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

β-Tubulin Isotype, TUBB4B, Regulates The Maintenance of Cancer Stem Cells

et al. 2021

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Recent advancements in cancer research have shown that cancer stem cell (CSC) niche is a crucial factor modulating tumor progression and treatment outcomes. It sustains CSCs by orchestrated regulation of several cytokines, growth factors, and signaling pathways. Although the features defining adult stem cell niches are well-explored, the CSC niche is poorly characterized. Since membrane trafficking proteins have been shown to be essential for the localization of critical proteins supporting CSCs, we investigated the role of TUBB4B, a probable membrane trafficking protein that was found to be overexpressed in the membranes of stem cell enriched cultures, in sustaining CSCs in oral cancer. Here, we show that the knockdown of TUBB4B downregulates the expression of pluripotency markers, depletes ALDH1A1+ population, decreases in vitro sphere formation, and diminishes the tumor initiation potential in vivo. As TUBB4B is not known to have any role in transcriptional regulation nor cell signaling, we suspected that its membrane trafficking function plays a role in constituting a CSC niche. The pattern of its expression in tissue sections, forming a gradient in and around the CSCs, reinforced the notion. Later, we explored its possible cooperation with a signaling protein, Ephrin-B1, the abrogation of which reduces the self-renewal of oral cancer stem cells. Expression and survival analyses based on the TCGA dataset of head and neck squamous cell carcinoma (HNSCC) samples indicated that the functional cooperation of TUBB4 and EFNB1 results in a poor prognosis. We also show that TUBB4B and Ephrin-B1 cohabit in the CSC niche. Moreover, depletion of TUBB4B downregulates the membrane expression of Ephrin-B1 and reduces the CSC population. Our results imply that the dynamics of TUBB4B is decisive for the surface localization of proteins, like Ephrin-B1, that sustain CSCs by their concerted signaling.

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βIII-tubulin overexpression in cancer: Causes, consequences, and potential therapies

Cited by 28 publications

References 168 publications

Microtubule Targeting Agents in Disease: Classic Drugs, Novel Roles

Microtubule Targeting Agents in Disease: Classic Drugs, Novel Roles

Dysregulation of Microtubule Nucleating Proteins in Cancer Cells

β-Tubulin Isotype, TUBB4B, Regulates The Maintenance of Cancer Stem Cells

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