How Do Cancer Cells "Starve" to Death?

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How Do Cancer Cells “Starve” to Death?

“Cell Research” How Do Cancer Cells “Starve” to Death?

Scientists Uncover the Mechanism of Low Glucose Activation of p53 to Induce Apoptosis in Cancer Cells.

When we think about cancer cells starving to death, we might picture them gasping for breath on the brink of extinction. However, the actual process of how cancer cells sense decreasing glucose levels and ultimately meet their demise remains largely unknown.

Today, a research team led by Dr. Shengcai Lin from Xiamen University’s School of Life Sciences published a groundbreaking study in the prestigious journal “Cell Research.” This study marks the first time the molecular mechanism behind how cells sense glucose changes and subsequently influence cell fate has been revealed [1].

Their research findings demonstrate that low glucose levels lead to a reduction in 3-phosphoglyceric acid (3-PGA) produced during glycolysis, which in turn promotes the binding of phosphoglycerate dehydrogenase (PHGDH) and the p53 protein. This results in the phosphorylation of the 46th amino acid of p53, activating p53’s ability to induce apoptosis, ultimately leading to the death of cancer cells.

In simple terms, PHGDH detects changes in 3-PGA levels, signaling variations in glucose levels and conveying this information to the p53 protein, ultimately determining the fate of cancer cells. Furthermore, the researchers suggest that this newly discovered mechanism may play a role in clearing cancer cells during early stages of cancer development.

This newfound mechanism may also explain why calorie restriction can help prevent cancer. So, feeling a little hungry from time to time might actually be a good thing.

Image: Screenshot from the research paper

A significant body of basic research has shown that calorie restriction can inhibit tumor growth. Some studies have linked changes in glucose levels with the levels and activity of p53 protein in tumor cells. For example, glucose restriction can lead to increased levels and activation of p53 [2,3].

From the perspective of p53 activation, the phosphorylation of serine residues at positions 15 and 20 maintains p53 stability, resulting in cell cycle arrest and halting tumor growth [4]. This is one of the reasons calorie restriction inhibits tumor growth.

However, p53 has another powerful anticancer function: inducing apoptosis in cells. Activating this function requires phosphorylation of the 46th serine residue of p53. Currently, it is unclear whether glucose and its glycolytic metabolites can activate this aspect of p53’s function.

Dr. Lin’s team first confirmed that glucose concentrations below 5mM indeed led to specific increases in the phosphorylation of the 46th serine residue of p53.

So, is it glucose itself or its metabolite, 3-phosphoglyceric acid (3-PGA), that affects the phosphorylation of p53’s 46th serine residue?

They conducted an extensive investigation into the glycolytic pathway and ultimately determined that it was not glucose but rather its metabolite, 3-phosphoglyceric acid (3-PGA), that regulated the phosphorylation of p53’s 46th serine residue.

Image: Glycolytic pathway

The next question was: who sensed changes in blood sugar through 3-PGA and ultimately regulated the phosphorylation of p53’s 46th serine residue?

Phosphoglycerate dehydrogenase (PHGDH) emerged from immunoprecipitation experiments. Subsequent experiments confirmed that PHGDH not only bound to 3-PGA but also directly interacted with the p53 protein.

More importantly, low glucose levels enhanced the interaction between PHGDH and p53, whereas the addition of 3-PGA inhibited the interaction between PHGDH and p53.

However, it is important to note that PHGDH, as an enzyme, has catalytic activity and plays a critical role in catalyzing the synthesis of serine from 3-PGA. Therefore, it was necessary to determine whether PHGDH’s binding ability or its catalytic activity influenced the phosphorylation of p53.

To address this, Dr. Lin’s team constructed various mutant forms of PHGDH, some with binding ability but lacking catalytic activity and others that completely lost their binding ability. The experimental results showed that as a direct sensor of 3-PGA, PHGDH only required its binding ability to transmit low glucose signals to p53, and its catalytic activity was not involved.

This finding contradicts previous understanding. Earlier research suggested that PHGDH promoted tumor growth by catalyzing the synthesis of serine, thus supporting tumor growth [5,6]. However, this study discovered that PHGDH’s binding function could regulate tumor growth through p53.

Image

As the revised understanding unfolded, attention turned to a study from 20 years ago.

In 2004, the team had discovered that UV-induced DNA damage led to the binding of acetyltransferase TIP60 and kinase HIPK2 to the scaffold protein AXIN. Together, they formed a complex (AXIN-TIP60-HIPK2-p53), with HIPK2 phosphorylating p53’s 46th serine residue [7].

So, did the phosphorylation of p53 induced by PHGDH sensing glucose changes converge with the phosphorylation of p53 induced by UV damage at this point?

Experimental data indicated that they did indeed converge.

Under low glucose conditions, the levels of TIP60, HIPK2, and AXIN in the cells all increased. Disrupting either AXIN or HIPK2 failed to elevate the phosphorylation levels of p53’s 46th serine residue under low glucose conditions.

In subsequent studies, Dr. Lin’s team quickly discovered that the binding of PHGDH to 3-PGA prevented the binding of PHGDH to AXIN, thereby inhibiting the formation of AXIN-TIP60-HIPK2-p53 and preventing the phosphorylation of p53’s 46th serine residue. This was reversed under low glucose conditions.

Thus, the regulation of p53’s 46th serine residue phosphorylation level by glucose levels and its impact on the mechanism of apoptosis regulation became clear.

Image: Schematic representation of the mechanism

In the final part of the study, Dr. Lin’s team verified the existence of this mechanism in a mouse model of liver cancer. It is worth noting that a negative correlation between 3-PGA and the phosphorylation of p53’s 46th serine residue was also observed in tumor tissues of liver cancer patients.

In summary, Dr. Lin’s research suggests that physiologically low blood sugar can autonomously initiate the formation of the PHGDH-AXIN-TIP60-HIPK2-p53 complex, increasing the phosphorylation of p53’s 46th serine residue and thereby inducing apoptosis.

It is worth noting that previous research has linked high blood sugar to liver cancer [8], while calorie-restricted diets can reduce the risk of liver cancer [9]. This discovery sheds light on these phenomena to some extent.

References:

[1].Wu YQ, Zhang CS, Xiong J, et al. Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate. Cell Res. 2023. doi:10.1038/s41422-023-00874-4

[2].Shim HS, Wei M, Brandhorst S, Longo VD. Starvation promotes REV1 SUMOylation and p53-dependent sensitization of melanoma and breast cancer cells. Cancer Res. 2015;75(6):1056-1067. doi:10.1158/0008-5472.CAN-14-2249

[3].Krstic J, Reinisch I, Schindlmaier K, et al. Fasting improves therapeutic response in hepatocellular carcinoma through p53-dependent metabolic synergism. Sci Adv. 2022;8(3):eabh2635. doi:10.1126/sciadv.abh2635

[4].He G, Zhang YW, Lee JH, et al. AMP-activated protein kinase induces p53 by phosphorylating MDMX and inhibiting its activity. Mol Cell Biol. 2014;34(2):148-157. doi:10.1128/MCB.00670-13

[5].Zhao JY, Feng KR, Wang F, et al. A retrospective overview of PHGDH and its inhibitors for regulating cancer metabolism. Eur J Med Chem. 2021;217:113379. doi:10.1016/j.ejmech.2021.113379

[6].Shunxi W, Xiaoxue Y, Guanbin S, Li Y, Junyu J, Wanqian L. Serine Metabolic Reprogramming in Tumorigenesis, Tumor Immunity, and Clinical Treatment. Adv Nutr. 2023;14(5):1050-1066. doi:10.1016/j.advnut.2023.05.007

[7].Rui Y, Xu Z, Lin S, et al. Axin stimulates p53 functions by activation of HIPK2 kinase through multimeric complex formation. EMBO J. 2004;23(23):4583-4594. doi:10.1038/sj.emboj.7600475

[8].Han H, Zhang T, Jin Z, et al. Blood glucose concentration and risk of liver cancer: systematic review and meta-analysis of prospective studies. Oncotarget. 2017;8(30):50164-50173. doi:10.18632/oncotarget.16816

[9].Li WQ, Park Y, McGlynn KA, et al. Index-based dietary patterns and risk of incident hepatocellular carcinoma and mortality from chronic liver disease in a prospective study. Hepatology. 2014;60(2):588-597. doi:10.1002/hep.27160