A very interesting new study. Leronlimab downregulates GRP78 via the PI3K/AKT pathway downregulation and the M2 to M1 machrophage shift. Besides lowering viral replication and metastasis, GRP78 downregulation may also explain why leronlimab can enhance chemotherapy by stopping DNA tumor cell repair. Lowering levels of GRP78 has been shown to reduce that repair.

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Study finds new, unexpected mechanism of cancer cell spread

The research, supported by the National Institutes of Health, centers on a cellular chaperone protein known as GRP78, which helps regulate the folding of other proteins inside cells. Previous studies from the same team, led by Amy S. Lee, PhD, professor of biochemistry and molecular medicine at the Keck School of Medicine of USC, have shown that when cells are under stress (due to COVID-19 or cancer), GRP78 gets hijacked, allowing viral invaders to replicate, and cancers to grow and resist treatment.

Lee and her colleagues have now made an unexpected discovery that may eventually enable scientists to protect cells from that hostile takeover. Typically, GRP78 resides in a part of the cell called the endoplasmic reticulum. But when cells are under stress, the chaperone protein migrates to the cell’s nucleus, where it alters gene activities and changes the behavior of the cell, allowing the cancer cells to become more mobile and invasive.

“Seeing GRP78 in the nucleus controlling gene expression is a total surprise,” said Lee, the study’s senior author and the Judy and Larry Freeman Chair in Basic Science research at the USC Norris Comprehensive Cancer Center. “When it comes to the basic mechanisms of cancer cells, this is something novel that, to my knowledge, no one has observed before.”

The team found that GRP78 binds to ID2, another cellular protein. ID2 typically suppresses genes (including EGFR), many of which allow cells to migrate. But when bound to GRP78, ID2 can no longer do its job. Without that suppression, cancer cells become more invasive.

https://keck.usc.edu/study-finds-new-unexpect...ll-spread/

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