Mechanistic insights into cancer drug resistance through optogenetic PI3K signaling hyperactivation

Yoshibumi Ueda; Yuri Miura; Nario Tomishige; Naotoshi Sugimoto; Megumi Murase; Genki Kawamura; Norihiko Sasaki; Toshiyuki Ishiwata; Takeaki Ozawa

doi:10.1016/j.chembiol.2022.10.002

Mechanistic insights into cancer drug resistance through optogenetic PI3K signaling hyperactivation

Cell Chem Biol. 2022 Nov 17;29(11):1576-1587.e5. doi: 10.1016/j.chembiol.2022.10.002. Epub 2022 Oct 25.

Authors

Yoshibumi Ueda¹, Yuri Miura², Nario Tomishige³, Naotoshi Sugimoto⁴, Megumi Murase⁵, Genki Kawamura⁵, Norihiko Sasaki⁶, Toshiyuki Ishiwata⁷, Takeaki Ozawa⁸

Affiliations

¹ Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan. Electronic address: yoshibumiueda@gmail.com.
² Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
³ UMR 7021 CNRS, Université de Strasbourg, Illkirch, France.
⁴ Department of Physiology, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan.
⁵ Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan.
⁶ Research Team for Geriatric Medicine, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
⁷ Division of Aging and Carcinogenesis, Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
⁸ Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan. Electronic address: ozawa@chem.s.u-tokyo.ac.jp.

PMID: 36288730
DOI: 10.1016/j.chembiol.2022.10.002

Abstract

Hyperactivation of phosphatidylinositol 3-kinase (PI3K) signaling is a prominent feature in cancer cells. However, the mechanism underlying malignant behaviors in the state remains unknown. Here, we describe a mechanism of cancer drug resistance through the protein synthesis pathway, downstream of PI3K signaling. An optogenetic tool (named PPAP2) controlling PI3K signaling was developed. Melanoma cells stably expressing PPAP2 (A375-PPAP2) acquired resistance to a cancer drug in the hyperactivation state. Proteome analyses revealed that expression of the antiapoptotic factor tumor necrosis factor alpha-induced protein 8 (TNFAIP8) was upregulated. TNFAIP8 upregulation was mediated by protein translation from preexisting mRNA. These results suggest that cancer cells escape death via upregulation of TNFAIP8 expression from preexisting mRNA even though alkylating cancer drugs damage DNA.

Keywords: PI3K signaling; PIP3; TNFAIP8; cancer drug resistance; optogenetics; phosphatidylinositol 3,4,5-trisphosphate.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Drug Resistance, Neoplasm
Neoplasms* / drug therapy
Optogenetics
Phosphatidylinositol 3-Kinases* / metabolism
Proto-Oncogene Proteins c-akt / metabolism
RNA, Messenger
Signal Transduction

Substances

Phosphatidylinositol 3-Kinases
RNA, Messenger
Proto-Oncogene Proteins c-akt