Erufosine Induces Autophagy and Apoptosis in Oral Squamous Cell Carcinoma: Role of the Akt-mTOR Signaling Pathway. Role of the Akt-mTOR Signaling Pathway.

Vaishali Kapoor, Maya M. Zaharieva, Martin R. Berger

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

3 Scopus citations

Abstract

The novel alkylphosphocholine erufosine exerts selective antitumor activity, but no myelotoxicity. Its mechanism of action is not fully understood, but is related to dephosphorylation of Akt and Rb. Our study revealed a novel mechanism underlying the anticancer activity of erufosine via downregulation of the mammalian target of rapamycin (mTOR) signaling cascade in oral squamous cell carcinoma cell lines. Erufosine showed dose-dependent cytotoxicity and simultaneously induced both autophagy and apoptosis via conversion of microtubule-associated protein light chain 3B-I (LC3B-I) to LC3B-II, caspase-3/7 activation, and Poly(ADP-ribose) polymerase (PARP) cleavage, respectively, in all the cell lines. In addition, G2 cell cycle arrest was observed along with cyclin D1 downregulation. These effects of erufosine were due to modulation of the mTOR signaling pathway. It readily downregulated p-Akt, p-Raptor, p-mTOR, and its downstream substrates, p-p70S6K and p-4EBP1. p-PRAS40 was reduced to undetectable levels. Moreover, blockage of p-mTOR expression by small interference RNA (siRNA) increased tumor cell sensitivity to erufosine, which was comparable to cisplatin, but higher than that of rapamycin. Furthermore, it showed additive effects on tumor cell cytotoxicity in combination with 5-flourouracil and cisplatin. Our study therefore indicated that erufosine induces apoptosis, autophagy, cell cycle arrest, and downregulates mTOR signaling in oral cancer cell lines. It has potential as an anticancer drug either alone or in combination with other chemotherapeutic agents.

Original languageEnglish
Title of host publicationAutophagy
Subtitle of host publicationCancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging
PublisherElsevier Inc.
Pages229-245
Number of pages17
Volume3
ISBN (Electronic)9780124055346
ISBN (Print)9780124055292
DOIs
StatePublished - Jan 31 2014

Keywords

  • Akt-mTOR Signaling Pathway
  • Alkylphosphocholines
  • Erufosine
  • MTOR
  • Oral Squamous Cell Carcinoma (OSCC)

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