Abstract
Sorafenib, a multi-tyrosine kinase inhibitor, kills more effectively the non-metastatic prostate cancer cell line 22Rv1 than the highly metastatic prostate cancer cell line PC3. In 22Rv1 cells, constitutively active STAT3 and ERK are targeted by sorafenib, contrasting with PC3 cells, in which these kinases are not active. Notably, overexpression of a constitutively active MEK construct in 22Rv1 cells stimulates the sustained phosphorylation of Bad and protects from sorafenib-induced cell death. In PC3 cells, Src and AKT are constitutively activated and targeted by sorafenib, leading to an increase in Bim protein levels. Overexpression of constitutively active AKT or knockdown of Bim protects PC3 cells from sorafenib-induced killing. In both PC3 and 22Rv1 cells, Mcl-1 depletion is required for the induction of cell death by sorafenib as transient overexpression of Mcl-1 is protective. Interestingly, co-culturing of primary cancer-associated fibroblasts (CAFs) with 22Rv1 or PC3 cells protected the cancer cells from sorafenib-induced cell death, and this protection was largely overcome by co-administration of the Bcl-2 antagonist, ABT737. In summary, the differential tyrosine kinase profile of prostate cancer cells defines the cytotoxic efficacy of sorafenib and this profile is modulated by CAFs to promote resistance. The combination of sorafenib with Bcl-2 antagonists, such as ABT737, may constitute a promising therapeutic strategy against prostate cancer.
Highlights
Since 1996, when the first attempt was made to profile the expression of tyrosine kinases in prostate cancer cells, significant progress has been made in mapping the signaling pathways important for the development of prostate cancer and in particular castration-resistant prostate cancer (CRPC).[2]
The Ras/Raf/MEK/ERK signaling cascade has a pivotal role in the molecular circuitry of CRPC, and the majority of the receptor tyrosine kinases (RTK) upregulated in prostate cancer have been shown to activate Ras.[5]
Several mechanisms have been proposed for the aberrant activation of the PI3K/AKT pathway, namely activating mutations in the catalytic subunit of PI3 K and AKT, loss of expression of PTEN and autocrine/paracrine signaling from the RTKs and nonreceptor tyrosine kinases (NRTK).[8,9]
Summary
Since 1996, when the first attempt was made to profile the expression of tyrosine kinases in prostate cancer cells, significant progress has been made in mapping the signaling pathways important for the development of prostate cancer and in particular CRPC.[2]. Several mechanisms have been proposed for the aberrant activation of the PI3K/AKT pathway, namely activating mutations in the catalytic subunit of PI3 K and AKT, loss of expression of PTEN and autocrine/paracrine signaling from the RTKs and NRTKs.[8,9] PTEN homozygous deletions have been detected in 20–30% of metastatic prostate cancer and more than 50% of prostate carcinomas exhibited increased AKT1 kinase activity.[10,11] AKT has been shown to have a key role in protecting cells from various types of apoptotic stimuli by phosphorylating and inhibiting downstream targets such as the Forkhead family transcription factors, which are known to regulate, among other proteins, the expression of the BH3-only protein Bim.[12]. Inhibitors that target tyrosine kinase signaling in both cancer cells and the tumor microenvironment might be efficient
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