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

Abstract:

:The present studies sought to further understand how the anti-folate pemetrexed and the multi-kinase inhibitor sorafenib interact to kill tumor cells. Sorafenib activated SRC, and via SRC the drug combination activated ERK1/2. Expression of dominant negative SRC or dominant negative MEK1 abolished drug-induced ERK1/2 activation, together with drug-induced autophagy, acidic lysosome formation, and tumor cell killing. Protein phosphatase 2A is an important regulator of the ERK1/2 pathway. Fulvestrant resistant MCF7 cells expressed higher levels of the PP2A inhibitor SET/I2PP2A, had lower endogenous PP2A activity, and had elevated basal ERK1/2 activity compared with their estrogen dependent counterparts. Overexpression of I2PP2A blocked drug-induced activation of ERK1/2 and tumor cell killing. PP2A can be directly activated by ceramide and SET/I2PP2A can be inhibited by ceramide. Inhibition of the de novo ceramide synthase pathway blocked drug-induced ceramide generation, PP2A activation and tumor cell killing. Collectively these findings demonstrate that ERK1/2 plays an essential role downstream of SRC in pemetrexed and sorafenib lethality and that PP2A plays an important role in regulating this process.

journal_name

Cancer Biol Ther

journal_title

Cancer biology & therapy

authors

Bareford MD,Hamed HA,Allegood J,Cruickshanks N,Poklepovic A,Park MA,Ogretmen B,Spiegel S,Grant S,Dent P

doi

10.4161/cbt.20562

subject

Has Abstract

pub_date

2012-07-01 00:00:00

pages

793-803

issue

9

eissn

1538-4047

issn

1555-8576

pii

20562

journal_volume

13

pub_type

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