PT  - JOURNAL ARTICLE
AU  - Thi Tuyet Trinh Phan
AU  - Yu-Chun Lin
AU  - Yu-Ting Chou
AU  - Chien-Wei Wu
AU  - Lih-Yuan Lin
TI  - Tumor Suppressor p53 Restrains Cancer Cell Dissemination by Modulating Mitochondrial Dynamics
AID  - 10.1101/2021.09.09.459707
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.09.09.459707
4099  - http://biorxiv.org/content/early/2021/11/18/2021.09.09.459707.short
4100  - http://biorxiv.org/content/early/2021/11/18/2021.09.09.459707.full
AB  - Tumor suppressor p53 plays a central role in preventing tumorigenesis. Here, we unravel how p53 modulates mitochondrial dynamics to restrain the metastatic properties of cancer cells. p53 inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling to attenuate the protein level of mitochondrial fission process 1 (MTFP1), which fosters the pro-fission dynamin-related protein 1 (Drp1) phosphorylation. This regulatory mechanism allows p53 to restrict cell migration and invasion governed by Drp1-mediated mitochondrial fission. Downregulating p53 expression or elevating the molecular signature of mitochondrial fission correlates with aggressive tumor phenotypes and poor prognosis in cancer patients. Upon p53 loss, exaggerated mitochondrial fragmentation stimulates the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling resulting in epithelial-to-mesenchymal transition (EMT)-like changes in cell morphology, accompanied by accelerated matrix metalloproteinase-9 (MMP9) expression and invasive cell migration. Notably, blocking the activation of mTORC1/MTFP1/Drp1/ERK1/2 axis completely abolishes the p53 deficiency-driven cellular morphological switch, MMP9 expression, and cancer cell dissemination. Our findings unveil a hitherto unrecognized mitochondria-dependent molecular mechanism underlying the metastatic phenotypes of p53-compromised cancers.Competing Interest StatementThe authors have declared no competing interest.