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Protein kinase Akt identified as arbiter of cancer stem cell fate

Date:
December 20, 2012
Source:
University of Pennsylvania School of Medicine
Summary:
The protein kinase Akt is a key regulator of cell growth, proliferation, metabolism, survival, and death. New research shows that Akt may be the key as to why cancer stem cells are so hard for the body to get rid of.

Signaling via the Akt serine/threonine protein kinase plays critical roles in the self-renewal of embryonic stem cells and their malignant counterpart, embryonal carcinoma cells.
Credit: Honglin Zhou, Perelman School of Medicine, University of Pennsylvania; Molecular Cell

The protein kinase Akt is a key regulator of cell growth, proliferation, metabolism, survival, and death. New work on Akt's role in cancer stem cell biology from the lab of senior author Honglin Zhou, MD, PhD and Weihua Li, co-first author, both from the Center for Resuscitation Sciences, Department of Emergency Medicine, Perelman School of Medicine, University of Pennsylvania, and Xiaowei Xu, Department of Pathology and Laboratory Medicine, appears in Molecular Cell.

The findings were also highlighted in Nature and Science reviews.

This new research shows that Akt may be the key as to why cancer stem cells are so hard for the body to get rid of. It has been documented that frequent hyperactivation of Akt kinases occurs in many types of human solid tumors and blood malignancies. Prior to this work, Akt was also shown to play a pivotal role in the fate of other types of stem cells, though those cellular mechanisms are still unclear.

"When I came to Penn in 2009, my lab first found that Akt regulates the activity of the protein Oct4," explains Zhou. Oct4 is one of the four transcriptional factors used to generate induced pluripotent stem cells, or iPS cells. In 2006, Kyoto University researcher and Nobel Prize winner Shinya Yamanaka expressed four proteins -- Oct 4 was one of the -- in mouse somatic cells to rewind their genetic clocks, converting them into embryonic-like iPS cells.

The biochemical experiments outlined in the Molecular Cell paper confirmed that Oct4 interacts directly with Akt and the adding of phosphate molecules to Oct4 by Akt regulates its stability, where it localizes in a cell, and its effect on gene expression. Akt phosphorylating Oct4 has the effect of making Oct4 migrate into the nucleus, where it interacts with other transcription factors and regulates target genes transcription.

The findings were further extended into embryonal carcinoma cells, which are derived from teratocarcinomas and often considered the malignant counterparts to embryonic stem cells (ESCs). The team showed that embryonal carcinoma cells with deregulated Akt activation and more phosphorylated Oct4 are more resistant to cell death signals such as ultraviolet irradiation and high glucose treatment.

Since Akt activation is often deregulated in cancer and Oct4 expression is upregulated in cancer stem cells of various types of cancer, the researchers are studying whether the Akt/Oct4 pathway plays similar roles in other types of cancer stem cells in addition to embryonal carcinoma cells. If true, Akt inhibitor may be developed as a new drug for killing cancer stem cells in cancer therapy.

The Molecular Cell work was been done in collaboration with Binghui Shen and Yingjie Wang from Zejiang University in China.


Story Source:

The above story is based on materials provided by University of Pennsylvania School of Medicine. Note: Materials may be edited for content and length.


Journal References:

  1. Yuanji Lin, Ying Yang, Weihua Li, Qi Chen, Jie Li, Xiao Pan, Lina Zhou, Changwei Liu, Chunsong Chen, Jianqin He, Hongcui Cao, Hangping Yao, Li Zheng, Xiaowei Xu, Zongping Xia, Jiangtao Ren, Lei Xiao, Lanjuan Li, Binghui Shen, Honglin Zhou, Ying-Jie Wang. Reciprocal Regulation of Akt and Oct4 Promotes the Self-Renewal and Survival of Embryonal Carcinoma Cells. Molecular Cell, 2012; 48 (4): 627 DOI: 10.1016/j.molcel.2012.08.030
  2. Felix Cheung. Stem cells: Caught in the act. Nature China, 2012; DOI: 10.1038/nchina.2012.74
  3. E. Andrianantoandro. Oct4 Connects Akt to Cancerous Stem Cells. Science Signaling, 2012; 5 (253): ec310 DOI: 10.1126/scisignal.2003837

Cite This Page:

University of Pennsylvania School of Medicine. "Protein kinase Akt identified as arbiter of cancer stem cell fate." ScienceDaily. ScienceDaily, 20 December 2012. <www.sciencedaily.com/releases/2012/12/121220144120.htm>.
University of Pennsylvania School of Medicine. (2012, December 20). Protein kinase Akt identified as arbiter of cancer stem cell fate. ScienceDaily. Retrieved July 29, 2014 from www.sciencedaily.com/releases/2012/12/121220144120.htm
University of Pennsylvania School of Medicine. "Protein kinase Akt identified as arbiter of cancer stem cell fate." ScienceDaily. www.sciencedaily.com/releases/2012/12/121220144120.htm (accessed July 29, 2014).

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