Loss of p53 Promotes Survival of Cancer Stem Cells

Cancer researchers have found that the cellular cleansing process known as mitophagy is linked to the development and progression of liver cancer.

Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. In addition to the selective removal of damaged mitochondria, mitophagy is also required to adjust mitochondrial numbers to changing cellular metabolic needs, for steady-state mitochondrial turnover, and during certain cellular developmental stages, such as during cellular differentiation of red blood cells.

Investigators at the University of Southern California (Los Angeles, USA) reported in the October 12, 2017, online edition of the journal Molecular Cell that mitophagy promoted the maintenance of hepatic cancer stem cells (CSCs) through the loss of the tumor suppressor protein p53, which was closely associated with the mitochondria.

When mitophagy was inhibited, the p53 protein on mitochondria was phosphorylated at serine-392 by the enzyme PINK1, a kinase associated with mitophagy. The phosphorylated p53 was then translocated into the nucleus, where it bound to the NANOG promoter. This binding prevented the OCT4 and SOX2 transcription factors from activating the expression of NANOG, a transcription factor critical for maintaining the stem cell properties and the self-renewal ability of CSCs, resulting in the reduction of hepatic CSC populations.

"Liver cancer is difficult to treat, and most patients who are diagnosed with it will die within a five-year period," said senior author Dr. Jing-Hsiung James Ou, professor of molecular microbiology and immunology at the University of Southern California. "My team has identified how liver cancer stem cells are maintained. Without these "seeds of cancer," liver tumors would shrink and eventually disappear. Now that we understand the molecular process, we will be able to target this pathway to stop the production of cancer stem cells. If cancer stem cells are gone, cancer is gone."

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