Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: The role of p53 and p21

José M. Escandell, Pawan Kaler, M. Carmen Recio, Takehiko Sasazuki, Senji Shirasawa, Leonard H. Augenlicht, José Luis Ríos, Lidija Klampfer

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Cucurbitacins have been shown to inhibit proliferation in a variety of cancer cell lines. The aim of this study was to determine their biological activity in colon cancer cell lines that do not harbor activated STAT3, the key target of cucurbitacin. In order to establish the role of activated kRas in the responsiveness of cells to cucurbitacins, we performed experiments in isogenic colon cancer cell lines, HCT116 and Hke-3, which differ only by the presence of an activated kRas allele. We compared the activity of 23, 24-dihydrocucurbitacin B (DHCB) and cucurbitacin R (CCR), two cucurbitacins that we recently isolated, with cucurbitacin I (CCI), a cucurbitacin with established antitumorigenic activity. We showed that cucurbitacins induced dramatic changes in the cytoskeleton (collapse of actin and bundling of tubulin microfilaments), inhibited proliferation and finally induced apoptosis of both HCT116 and Hke-3 cells. However, the presence of oncogenic kRas significantly decreased the sensitivity of cells to the three cucurbitacins tested, CCR, DHCB and CCI. We confirmed that mutational activation of kRas protects cells from cucurbitacin-induced apoptosis using nontransformed intestinal epithelial cells with inducible expression of kRasV12. Cucurbitacins induced the expression of p53 and p21 predominantly in HCT116 cells that harbor mutant Ras. Using HCT116 cells with targeted deletion of p53 or p21 we confirmed that p53 and p21 protect cells from apoptosis induced by cucurbitacins. These results demonstrated that sensitivity of human colon cancer cell lines to cucurbitacins depends on the kRas and p53/p21 status, and established that cucurbitacins can exert antitumorigenic activity in the absence of activated STAT3.

Original languageEnglish (US)
Pages (from-to)198-207
Number of pages10
JournalBiochemical Pharmacology
Volume76
Issue number2
DOIs
StatePublished - Jul 15 2008

Fingerprint

Cucurbitacins
Colonic Neoplasms
Cells
Apoptosis
HCT116 Cells
Cell Line
Ports and harbors
Actin Cytoskeleton
Tubulin
Bioactivity

Keywords

  • Apoptosis
  • Colon cancer
  • Cucurbitacin
  • kRas
  • p53

ASJC Scopus subject areas

  • Pharmacology

Cite this

Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis : The role of p53 and p21. / Escandell, José M.; Kaler, Pawan; Recio, M. Carmen; Sasazuki, Takehiko; Shirasawa, Senji; Augenlicht, Leonard H.; Ríos, José Luis; Klampfer, Lidija.

In: Biochemical Pharmacology, Vol. 76, No. 2, 15.07.2008, p. 198-207.

Research output: Contribution to journalArticle

Escandell, JM, Kaler, P, Recio, MC, Sasazuki, T, Shirasawa, S, Augenlicht, LH, Ríos, JL & Klampfer, L 2008, 'Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: The role of p53 and p21', Biochemical Pharmacology, vol. 76, no. 2, pp. 198-207. https://doi.org/10.1016/j.bcp.2008.05.004
Escandell, José M. ; Kaler, Pawan ; Recio, M. Carmen ; Sasazuki, Takehiko ; Shirasawa, Senji ; Augenlicht, Leonard H. ; Ríos, José Luis ; Klampfer, Lidija. / Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis : The role of p53 and p21. In: Biochemical Pharmacology. 2008 ; Vol. 76, No. 2. pp. 198-207.
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