دورية أكاديمية
Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells
العنوان: | Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells |
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المؤلفون: | Hiu‑Fung Yuen, Olga Abramczyk, Grant Montgomery, Ka‑Kui Chan, Yu‑Han Huang, Takehiko Sasazuki, Senji Shirasawa, Srivastava Gopesh, Kwok‑Wah Chan, Dean Fennell, Pasi Janne, Mohamed El‑Tanani, James T. Murray |
المصدر: | Bioscience Reports, Vol 32, Iss 4 (2012) |
بيانات النشر: | Portland Press, Biochemical Society, 2012. |
سنة النشر: | 2012 |
المجموعة: | LCC:Life LCC:Microbiology |
مصطلحات موضوعية: | Akt, cancer cell, c-Met, K-Ras, mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase (MEK), phosphoinositide 3-kinase (PI3K), Life, QH501-531, Microbiology, QR1-502 |
الوصف: | Inhibition of the PI3K (phosphoinositide 3-kinase)/Akt/mTORC1 (mammalian target of rapamycin complex 1) and Ras/MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase]/ERK pathways for cancer therapy has been pursued for over a decade with limited success. Emerging data have indicated that only discrete subsets of cancer patients have favourable responses to these inhibitors. This is due to genetic mutations that confer drug insensitivity and compensatory mechanisms. Therefore understanding of the feedback mechanisms that occur with respect to specific genetic mutations may aid identification of novel biomarkers that predict patient response. In the present paper, we show that feedback between the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways is cell-line-specific and highly dependent on the activating mutation of K-Ras or overexpression c-Met. We found that cell lines exhibited differential signalling and apoptotic responses to PD184352, a specific MEK inhibitor, and PI103, a second-generation class I PI3K inhibitor. We reveal that feedback from the PI3K/Akt/mTORC1 to the Ras/MEK/ERK pathway is present in cancer cells harbouring either K-Ras activating mutations or amplification of c-Met but not the wild-type counterparts. Moreover, we demonstrate that inhibition of protein phosphatase activity by OA (okadaic acid) restored PI103-mediated feedback in wild-type cells. Together, our results demonstrate a novel mechanism for feedback between the PI3K/Akt/mTORC1 and the Ras/MEK/ERK pathways that only occurs in K-Ras mutant and c-Met amplified cells but not the isogenic wild-type cells through a mechanism that may involve inhibition of a specific endogenous phosphatase(s) activity. We conclude that monitoring K-Ras and c-Met status are important biomarkers for determining the efficacy of PI103 and other PI3K/Akt inhibitors in cancer therapy. |
نوع الوثيقة: | article |
وصف الملف: | electronic resource |
اللغة: | English |
تدمد: | 0144-8463 1573-4935 |
Relation: | http://www.bioscirep.org/bsr/032/0413/bsr0320413.htm; https://doaj.org/toc/0144-8463; https://doaj.org/toc/1573-4935 |
DOI: | 10.1042/BSR20120050 |
URL الوصول: | https://doaj.org/article/9295872ba0ff442d8eb285982b7d1cf0 |
رقم الأكسشن: | edsdoj.9295872ba0ff442d8eb285982b7d1cf0 |
قاعدة البيانات: | Directory of Open Access Journals |
تدمد: | 01448463 15734935 |
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DOI: | 10.1042/BSR20120050 |