Interplay between PI3K/Akt and MAPK signaling pathways in DNA-damaging drug-induced apoptosis

Eung Ryoung Lee, Jang Yong Kim, Yong Jin Kang, Jae Yeon Ahn, Jung Hyun Kim, Bong Woo Kim, Hye Yeon Choi, Mi Young Jeong, Ssang Goo Cho

Research output: Contribution to journalArticlepeer-review

133 Scopus citations


In order to elucidate the role of the mitogen-activated protein kinases, including JNK, p38 MAPK and ERK, as well as the survival-associated PI3K/Akt signaling pathway, in the response to chemotherapy, we have conducted a comparative study regarding the effects of doxorubicin on these pathways. Doxorubicin was determined to elicit the apoptosis of NIH3T3 cells in a dose-dependent manner. Prior to cell death, both Akt and p38 MAPK were transiently activated, and subsequently inactivated almost wholly, whereas ERK and JNK evidenced sustained activations in response to the drug treatment. The inhibition of PI3K/Akt and p38 MAPK both accelerated and enhanced doxorubicin-induced apoptosis and ERK inhibition apparently exerted negative effect on apoptosis. The modulation of PI3K/Akt activation by treatment of LY294002 or expression of Akt mutants such as Akt-DN or Myr-Akt exerted a significant effect on the activation of ERK1/2. We also observed that PI3K/Akt and sustained ERK activation were associated intimately with the etoposide-induced apoptosis. Taken together, our results clearly suggest that the differential regulation of the PI3K/Akt, ERK1/2, and p38 MAPK signaling pathways are crucial in the context of DNA-damaging drug-induced apoptosis, and this has compelled us to propose that the sustained activation of ERK1/2 pathway may be generally involved in the apoptosis induced by anticancer DNA-damaging drugs, including doxorubicin and etoposide.

Original languageEnglish (US)
Pages (from-to)958-968
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Issue number9
StatePublished - Sep 2006
Externally publishedYes


  • Akt
  • Apoptosis
  • DNA-damaging drug
  • Doxorubicin
  • ERK
  • Etoposide

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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