Protein synthesis control in cancer: selectivity and therapeutic targeting

Abstract

Translational control of mRNAs is a point of convergence for many oncogenic signals through which cancer cells tune protein expression in tumorigenesis. Cancer cells rely on translational control to appropriately adapt to limited resources while maintaining cell growth and survival, which creates a selective therapeutic window compared to non-transformed cells. In this review, we first discuss how cancer cells modulate the translational machinery to rapidly and selectively synthesize proteins in response to internal oncogenic demands and external factors in the tumor microenvironment. We highlight the clinical potential of compounds that target different translation factors as anti-cancer therapies. Next, we detail how RNA sequence and structural elements interface with the translational machinery and RNA-binding proteins to coordinate the translation of specific pro-survival and pro-growth programs. Finally, we provide an overview of the current and emerging technologies that can be used to illuminate the mechanisms of selective translational control in cancer cells as well as within the microenvironment.

Oxidation-controlled, Strain-Promoted Tellurophene-Alkyne Cycloaddition (OSTAC): A Bioorthogonal Reaction for Fast and Selective Protein Conjugation

“…in the presence of endo-bicyclo[6.1.0]non-4-yn-9-yl methanol (endo-BCN-OH) rapidly and cleanly forms the desired benzocyclooctane product 4 under ambient conditions. Analysis of the reaction by 1 H NMR indicated complete conversion to a new multiplet at 7.0 ppm, with no evidence of any reversion to Te(II) tellurophene or dimer formation (Fig. 3c.…”

“…Silica harbouring product was removed, sonicated in 10 mL 1:2 MeOH/H2O, and centrifuged at 21.1 x g to obtain a clear aqueous solution, which was lyophilized to yield a solid consisting mostly of dimer and small amounts of NCS-derived impurities. 1 H NMR (500 MHz, D2O, 298 K) δ 7.74 and 7.72 (1H, 2 s, vinyl H), 7.54-7.18 (4H, m, aryl H), 4.48 (1H, 2 overlapping t, J = 6.4 Hz, Hα), 4.38 (1H, 2 overlapping t, J = 8.0 Hz, Hα′), 3.93 (1H, 2 overlapping hept., J = 6.6 Hz, i Pr-CH(CH3)2), 3.75 (1H, 2 overlapping hept., J = 6.6 Hz, i Pr′-CH(CH3)2), 3.33-2.91 (4H, m, Hβ), 2.05, 2.04, 1.98, and 1.95 (6 H, 4 s, N-Ac-CH3), 1.22-0.69 (12H, m, i Pr-CH(CH3)2). 13 Reaction of 2 with N-methylmaleimide (NMM).…”

“…Product was extracted from silica by repeated sonication in MeOH and centrifugation, followed by passage of the MeOH extract through a 0.45 μm PTFE syringe filter, and concentration in vacuo (5.7 mg white solid, 58% isolated; mixture of diastereomers). 1 H NMR (600 MHz, MeOD, 328 K) δ 7.04-6.94 (3 H, m, aryl H), 4.48 and 4.47 (1H, 2 overlapping t, J = 7.6 Hz, Hα), 3.87 and 3.86 (1H, 2 overlapping hept., J = 6.7 Hz, i Pr-CH(CH3)2), 3.69-3.58 (2H, m, HO-CH2cyclopropyl), 3.20-2.75 (6H, m, 2 Hβ and 4 cyclooctane benzylic H), 2.34-2.15 (2H, m, 2 cyclooctane homobenzylic H), 1.94 and 1.93 (3H, 2 s, N-Ac-CH3), 1.48 (2H, broad s, 2 cyclooctane homobenzylic H), 1.07 (3H, 2 overlapping d, J = 6.6 Hz, i Pr-CH(CH3)2), 1.00 (1H, m, HO-CH2-CH(CH)2-) 0.92 (3H, 2 overlapping d, J = 6.6 Hz, i Pr-CH(CH3)2), 0.84 (2H, broad s, 2 bicyclo[6.1.0]nonane bridgehead H). 13 C NMR (125 MHz, MeOD, 298 K) δ 172.85, 172.82, 172.…”

“…Strict control of protein synthesis is critical to proper cellular function, while aberrant expression leads to toxicity and disease. [1][2][3] The ability to characterize proteomic changes in response to environmental and physiological signals is key to addressing many questions in biology and medicine. Although many methodologies have been developed to track translation and to identify nascent proteins [4][5][6][7] , these experiments remain non-trivial.…”

KAT8-catalyzed lactylation contributes to eEF1A2-mediated protein synthesis and colorectal carcinogenesis

“…Protein synthesis is one of the most energy-consuming and tightly-controlled processes in creatures 35 . Proper regulation of protein synthesis ensures creatures respond appropriately to various biological demands while the dysregulation in translation leads to aberrant pathways activation including oncogenic signaling in neoplasia [36][37][38] . Post-translational modifications play vital roles in this process.…”