In tumors with mutational activation of both PI3K/AKT and MEK/ERK pathways, inhibition of either pathway alone has minor or negligible effects on cell survival and tumor growth [31]

In tumors with mutational activation of both PI3K/AKT and MEK/ERK pathways, inhibition of either pathway alone has minor or negligible effects on cell survival and tumor growth [31]. level of translation by convergent activation of the mTORC1/4E-BP1/eIF4E signaling axis. In addition, loss of 4E-BP1 function induces epithelialCmesenchymal transition and increases metastatic capability of malignancy cells by translational activation of Snail. Continuous translation of survivin and Snail is usually important for colorectal cancer progression to metastasis. Herein we discuss our findings concerning deregulation of translation in cancer progression and metastasis and spotlight 4E-BP1 as a potential biomarker and therapeutic target. and is also a common oncogenic event in a variety of cancers [17, 18]. Moreover, the AKT and ERK pathways are concurrently activated by individual mutations in many human tumors. For instance, and mutation; and mutation; and and mutation occur simultaneously in colorectal carcinoma, thyroid carcinoma and melanoma, respectively [19C23]. Deregulated AKT and ERK pathways are proven to be actively involved in maintaining malignant properties in tumor cells and promoting cancer progression and metastasis [24, 25]. Thus, a number of small molecule inhibitors targeting components of these two pathways Isotetrandrine have been aggressively developed for the treatment of cancers [17, 18, 26, 27]. Preclinical studies and clinical trials with selective PI3K and AKT inhibitors have shown that tumors with mutations are likely to be dependent on the PI3K/AKT pathway and are sensitive to inhibition of that pathway [28C30]. We found that in mutant tumors, the AKT dependence of 4E-BP1 phosphorylation is usually closely correlated with tumor growth [28, 31]. On the other hand, the BRAF inhibitor vemurafenib or the MEK inhibitor trametinib produces high response rates in mutant BRAF V600E-driven melanoma [32, 33]. However, tumor cells with or mutations are not all sensitive to the inhibitors of PI3K or AKT [31, 34]. Similarly, mutant or tumors are not usually dependent on ERK signaling and sensitive to the BRAF and MEK inhibitors [31, 35, 36]. We exhibited that coexistent mutation renders mutant tumors impartial of PI3K/AKT signaling, whereas mutation uncouples tumor growth from MEK/ERK and mutant signaling [31, 36]. In tumors with mutational activation of both PI3K/AKT and MEK/ERK pathways, inhibition of either pathway alone has minor or negligible effects on cell survival and tumor growth [31]. However, combined inhibition of both pathways effectively induces apoptosis and suppresses tumor growth [31]. These data suggest that AKT and ERK pathways may activate a common set of downstream targets that integrate their function in tumors, thus reducing oncogenic dependency on AKT or ERK signaling pathway and causing resistance to inhibition of either pathway alone. 4E-BP1 is usually a key effector of the oncogenic action of AKT and ERK signaling pathways in tumorigenesis We discovered that redundant Isotetrandrine phosphorylation of 4E-BP1 with concomitant activation of cap-dependent translation mediated by the AKT and ERK pathways is usually associated with the resistance to targeted inhibition of either pathway alone in tumors with coexistent pathway activation [31]. In the experimental model of colorectal cancer (CRC) with coexistent and mutations, 4E-BP1 phosphorylation is usually unresponsive or less affected by inhibition of either AKT or ERK pathway alone. However, combined inhibition of both pathways effectively inhibits 4E-BP1 phosphorylation, which in turn activates 4E-BP1 binding to the eIF4E-mRNA cap complex and thus represses eIF4E-initiated cap-dependent translation, with an associated synergistic induction of apoptosis and suppression of tumor growth [31]. Moreover, using a non-phoshorylated mutant 4E-BP1 allele with four known phosphorylation sites (T37, T46, S65, T70) substituted with alanine (4E-BP1-4A), which causes constitutive binding to eIF4E and inhibition of cap-dependent translation, we were able to show that this active 4E-BP1 mutant exerts comparable inhibitory effects on CRC tumor growth as does the combined inhibition of AKT and ERK pathways. Others studies also show that the active 4E-BP1 can block tumorigenesis in mutant breast malignancy, AKT-driven lymphoma and mutant non-small cell lung.Furthermore, incomplete inhibition of 4E-BP1 phosphorylation or mTOR-independent phosphorylation of 4E-BP1 is believed to be an additional mechanism that causes tumor cell resistance to mTOR inhibitors [54C57]. and metastasis and spotlight 4E-BP1 as a potential biomarker and therapeutic target. and is also a common oncogenic event in a variety of cancers [17, 18]. Moreover, the AKT and ERK pathways are concurrently activated by individual mutations in many human tumors. For instance, and mutation; and mutation; and and mutation occur simultaneously in colorectal carcinoma, thyroid carcinoma and melanoma, respectively [19C23]. Deregulated AKT and ERK pathways are proven to be actively involved in maintaining malignant properties in tumor cells and promoting Isotetrandrine cancer progression and metastasis [24, 25]. Thus, a number of small molecule inhibitors targeting components of these two pathways have been aggressively developed for the treatment of cancers [17, 18, 26, 27]. Preclinical studies and clinical trials with selective PI3K and AKT inhibitors have shown that tumors with mutations are likely to be dependent on the PI3K/AKT pathway and are sensitive to inhibition of that pathway [28C30]. We found that in mutant tumors, the AKT dependence of 4E-BP1 phosphorylation is usually closely correlated with tumor growth [28, 31]. On the other hand, the BRAF inhibitor vemurafenib or the MEK inhibitor trametinib produces high response rates in mutant BRAF V600E-driven melanoma [32, 33]. However, tumor cells with or mutations are not all sensitive to the inhibitors of PI3K or AKT [31, 34]. Similarly, mutant or tumors are not always dependent on ERK signaling and sensitive to the BRAF and MEK inhibitors [31, 35, 36]. We exhibited that coexistent mutation renders mutant tumors impartial of PI3K/AKT signaling, whereas mutation uncouples tumor growth from MEK/ERK and mutant signaling [31, 36]. In tumors with mutational activation of both PI3K/AKT and MEK/ERK pathways, inhibition of either pathway alone has minor or negligible effects on cell survival and tumor growth [31]. However, combined inhibition of both pathways effectively induces apoptosis and suppresses tumor growth [31]. These data suggest that AKT and ERK pathways may activate a common set of KIP1 downstream targets that integrate their function in tumors, thus reducing oncogenic dependency on AKT or ERK signaling pathway and causing resistance to inhibition of either pathway alone. 4E-BP1 is usually a key effector of the oncogenic action of AKT and ERK signaling pathways in tumorigenesis We discovered that redundant phosphorylation of 4E-BP1 with concomitant activation of cap-dependent translation mediated by the AKT and ERK pathways is usually associated with the resistance to targeted inhibition of either pathway alone in tumors with coexistent pathway activation [31]. In the experimental model of colorectal cancer (CRC) with coexistent and mutations, 4E-BP1 phosphorylation is usually unresponsive or less affected by inhibition of either AKT or ERK pathway alone. However, combined inhibition of both pathways effectively inhibits 4E-BP1 phosphorylation, which in turn activates 4E-BP1 binding to the eIF4E-mRNA cap complex and thus represses eIF4E-initiated cap-dependent translation, with an associated synergistic induction of apoptosis and suppression of tumor growth [31]. Moreover, using a non-phoshorylated mutant 4E-BP1 allele with four known phosphorylation sites (T37, T46, S65, T70) substituted with alanine (4E-BP1-4A), which causes constitutive binding to eIF4E and inhibition of cap-dependent translation, we were able to show that this active 4E-BP1 mutant exerts comparable inhibitory effects on CRC tumor growth as does the combined inhibition of AKT and ERK pathways. Others studies also show that the active 4E-BP1 can block tumorigenesis in mutant breast malignancy, AKT-driven lymphoma and mutant non-small cell lung cancer [37C39]. In contrast, knockdown of 4E-BP1 expression or overexpression of eIF4E profoundly attenuates dependence of colon tumors on activated AKT and ERK signaling for translation and survival [31]. In addition, we further.