Phase separation orchestrates cancer signaling. ACA-28, a novel ERK signaling modulator with anti-cancer activity, regulates stress granules.

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  • Sugiura Reiko
    Laboratory of Molecular Pharmacogenomics, Department of Pharmaceutical Sciences, Kindai University

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  • 「相分離は癌化シグナルを制御する」～新規ERKシグナル調節薬ACA-28と相分離の関わり～

Abstract

<p>Stress granule (SG) is a conserved cellular strategy that copes with stress-related damage and promotes cell survival. SGs form through a process of liquid-liquid phase separation (LLPS). Cellular signaling also employs SG assembly as a mechanism for controlling cell survival and cell death by spatial compartmentalization of signal-transducing factors, thus indicating that SGs constitute signaling hubs that can rewire cancer signal transduction.  Recently, SGs have attracted strong attention as a promising target for cancer treatment because of their involvement in various aspects of cancer progression, ranging from cancer formation, and metastasis as well as drug resistance. Here, I will report our discoveries of the role of SGs as a safeguard to prevent excess hyperactivation of PKC/MAPK signaling as well as a novel anti-cancer compound ACA-28 with a unique property. ACA-28 was shown to inhibit the proliferation of several cancer cell lines with high ERK, including melanoma and pancreatic cancer. Importantly, ACA-28 was shown to induce cancer cell-specific apoptosis and impact SG formation by stimulating ERK activity. We will discuss fundamental aspects of LLPS as a new paradigm for cancer biology and then focus on recent advances in the role of SGs in cancer signaling, especially therapeutic strategies targeting SGs.</p>

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