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Professor Koji Okamoto Leads Breakthrough Research in Colorectal Cancer Resistance

On May 23, 2023 (Tuesday), In a pioneering collaboration, Professor Koji Okamoto from Teikyo University's Advanced Comprehensive Research Organization, along with Ryuji Hamamoto, Director of the National Cancer Center Research Institute, and Shuzo Kaneko, Unit Director, announced a groundbreaking research venture on May 23, 2023. Their study has uncovered a novel molecular mechanism crucial in maintaining resistance to anticancer drugs. Resistance in cancer cells poses a formidable challenge in treatment, often leading to recurrence post-treatment. Researchers have long sought a solution to this enigma. The newly revealed mechanism revolves around autophagy, a process responsible for breaking down intracellular proteins within lysosomes. It plays a pivotal role in maintaining the body's equilibrium by curbing the accumulation of abnormal proteins and recycling them, especially in low-nutrient environments.

However, autophagy's involvement in cancer progression has remained a subject of investigation. The research team's findings indicate that the activation of autophagy prompts the emergence of anticancer drug-resistant cells marked by the presence of the transcription factor PROX1. Additionally, they unveiled a hitherto unknown molecular mechanism wherein PROX1 orchestrates the maintenance of properties in anticancer drug-resistant cells through a feedback loop with the kinase complex mTORC1, a suppressor of autophagy. Excitingly, the team also found that the combined application of existing anticancer drugs and autophagy inhibitors demonstrates a synergistic effect in inhibiting colorectal cancer. This discovery is poised to pave the way for the development of innovative inhibitors targeting the autophagy pathway, as well as novel treatment modalities for colorectal cancer. The results of this groundbreaking research were unveiled in the online edition of the esteemed US scientific journal Cell Reports on May 23, 2023, Eastern Standard Time. This revelation stands as a beacon of hope in the relentless fight against colorectal cancer, offering prospects of more effective and targeted therapies for patients worldwide.
Autophagy is one of the mechanisms for degrading intracellular proteins in lysosomes. It is said to be involved in the maintenance of homeostasis of the body by suppressing the accumulation of abnormal proteins in cells and recycling proteins in low-nutrient environments. On the other hand, autophagy is also believed to be involved in cancer progression. The research group found that activation of autophagy induces anticancer drug-resistant cells that are positive for the transcription factor PROX1. In addition, we clarified a new molecular mechanism that PROX1 works to maintain the properties of anticancer drug-resistant cells through feedback control via the kinase complex mTORC1, which suppresses autophagy. Furthermore, we found that the combination of existing anticancer drugs and autophagy inhibitors synergistically inhibits colorectal cancer. The results of this research are expected to lead to the development of new inhibitors targeting the autophagy pathway and new treatments for colorectal cancer.
The results of this research were published in the online version of the US scientific journal Cell Reports on May 23, 2023 (Eastern Standard Time).

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