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Sorafenib and pemetrexed toxicity in cancer cells is mediated via SRC-ERK signaling

M Danielle Bareford1, Hossein A Hamed, Jeremy Allegood

  • 1Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, USA.

Cancer Biology & Therapy
|June 8, 2012
PubMed

Insights

The combination of pemetrexed and sorafenib kills tumor cells by activating the ERK1/2 pathway. Protein phosphatase 2A (PP2A) and ceramide are crucial for this drug-induced cell death.

Area of Science:

  • Oncology
  • Molecular Cell Biology

Background:

  • The anti-folate pemetrexed and multi-kinase inhibitor sorafenib are used in cancer therapy.
  • Understanding drug interactions is key to improving cancer treatment efficacy.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which pemetrexed and sorafenib synergistically induce tumor cell death.
  • To investigate the roles of SRC, ERK1/2, protein phosphatase 2A (PP2A), and ceramide in this process.

Main Methods:

  • Utilized dominant-negative SRC and MEK1 to assess pathway involvement.
  • Investigated the role of PP2A and its inhibitor SET/I2PP2A in drug response.
  • Examined the impact of ceramide generation and the de novo ceramide synthase pathway.

Main Results:

  • Sorafenib activates SRC, leading to ERK1/2 activation, which is essential for drug-induced cell killing, autophagy, and lysosome acidification.
  • Elevated SET/I2PP2A levels in resistant cells correlate with reduced PP2A activity and basal ERK1/2 activity.
  • Inhibition of ceramide synthesis blocks ceramide generation, PP2A activation, and tumor cell death.

Conclusions:

  • ERK1/2 signaling, downstream of SRC, is critical for pemetrexed and sorafenib-mediated tumor cell lethality.
  • PP2A plays a regulatory role in this pathway, influenced by ceramide and its inhibitor SET/I2PP2A.

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