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Assay for Phosphorylation and Microtubule Binding Along with Localization of Tau Protein in Colorectal Cancer Cells
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Tubulin-binding anticancer polysulfides induce cell death via mitotic arrest and autophagic interference in

Esma Yagdi Efe1, Aloran Mazumder2, Jin-Young Lee2

  • 1Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.

Cancer Letters
|September 26, 2017
PubMed

Insights

Dibenzyl tetrasulfide (DBTTS) inhibits colorectal cancer (CRC) by targeting tubulin and interfering with autophagy. This compound shows therapeutic potential in preclinical models, offering new avenues for CRC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Polysulfanes exhibit chemopreventive properties against gastrointestinal tumors.
  • Diallyl tetrasulfide and its derivative, dibenzyl tetrasulfide (DBTTS), are identified as mitotic inhibitors and apoptosis inducers.

Purpose of the Study:

  • To investigate the therapeutic application of dibenzyl tetrasulfide (DBTTS) in colorectal cancer (CRC).
  • To elucidate the mechanisms underlying DBTTS's efficacy, including tubulin binding, mitotic inhibition, and autophagy modulation.

Main Methods:

  • MALDI-TOF-MS analysis to identify DBTTS as a reversible tubulin binder.
  • In cellulo validation of α-tubulin degradation.
  • Cell-based assays using BRAF(V600E)-mutated HT-29 and KRAS(G12V)-mutated SW480/620 cells to assess differential responses.
  • siRNA-mediated p62 inhibition and in silico analysis of patient data.
  • In vitro spheroid and colony formation assays, and in vivo zebrafish xenograft models.

Main Results:

  • DBTTS was confirmed as a reversible tubulin binder, leading to α-tubulin degradation.
  • HT-29 cells (BRAF-mutated) showed resistance to DBTTS with prolonged mitotic arrest, linked to autophagy impairment and p62 accumulation.
  • SW480/620 cells (KRAS-mutated) exhibited earlier apoptosis induction with intact autophagy.
  • In silico analysis revealed that higher p62 expression and reduced autophagic flux correlate with better survival in CRC patients.
  • DBTTS inhibited spheroid and colony formation in CRC cells and demonstrated efficacy in HT-29 zebrafish xenografts.

Conclusions:

  • DBTTS demonstrates therapeutic potential against colorectal cancer by inducing mitotic arrest and apoptosis.
  • The compound's efficacy is modulated by cellular autophagic capacity and p62 protein levels, suggesting a mechanism involving autophagy interference.
  • DBTTS represents a promising agent for CRC treatment, particularly in specific genetic contexts, warranting further clinical investigation.
Keywords:
Autophagic fluxCell deathDiallyl sulfideMitotic arrestZebrafish xenografts

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