- Title
- Inhibition of MEK sensitizes paclitaxel-induced apoptosis of human colorectal cancer cells by downregulation of GRP78
- Creator
- Mhaidat, Nizar M.; Alali, Feras Q.; Matalqah, Sina M.; Matalka, Ismail I.; Jaradat, Saied A.; Al-Sawalha, Nour A.; Thorne, Rick F.
- Relation
- Anti-Cancer Drugs Vol. 20, Issue 7, p. 601-606
- Publisher Link
- http://dx.doi.org/10.1097/CAD.0b013e32832e3120
- Publisher
- Lippincott Williams & Wilkins
- Resource Type
- journal article
- Date
- 2009
- Description
- Here we report that paclitaxel induces variable degrees of apoptosis in human colorectal cancer cells. Paclitaxel induces multiple arms of the endoplasmic reticulum stress response, including upregulation of the 78-kDa glucose-regulatory protein (GRP78) and eukaryotic initiation factor [alpha] phosphorylation. Inhibition of the MEK/ERK pathway sensitized colorectal cancer cells to paclitaxel-induced apoptosis. A similar result was obtained by the inhibition of GRP78 using small interfering RNA molecules. Knockdown of MEK resulted in a significant downregulation of paclitaxel-induced upregulation of GRP78 indicating that activation of GRP78 is a downstream event of MEK/ERK pathway activation. These results indicate that GRP78 might be a novel mechanism underlying the resistance of colorectal cancer cells to microtubule-targeting drugs. A combination of compounds capable of suppressing GRP78 might be a golden approach for improving the effectiveness of taxanes.
- Subject
- apoptosis; colon cancer; 78-kDa glucose-regulatory protein; paclitaxel; unfolded protein response
- Identifier
- uon:8335
- Identifier
- http://hdl.handle.net/1959.13/917519
- Identifier
- ISSN:0959-4973
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