Increased understanding of the Skp2 gene¹ and its relation to cellular² senescence（衰老） may lead to the development of novel agents that can suppress（抑制，镇压） tumor³ development in common types of cancer, researchers from The University of Texas M. D. Anderson Cancer Center and Memorial Sloan-Kettering Cancer Center report in the journal Nature. Skp2 is involved in promoting cell cycle（细胞周期） regulation, cell proliferation（增殖，繁殖） , cell growth and the formation of tumors, and it is overexpressed in a variety of human cancers, according to lead author Hui-Kuan Lin, Ph.D., an assistant professor in M. D. Anderson's Department of Molecular⁴ and Cellular Oncology.

Lin and colleagues found that inactivating⁵ Skp2 after oncogenes（致癌基因） are overexpressed stifles⁶（窒息，扼杀） cancer growth by causing senescence - the irreversible loss of a cell's ability to divide and grow. Harnessing the power of cellular senescence to push rapidly dividing cells into a dormant⁷（静止的，休眠的） state might provide another way to prevent or control common malignancies（恶性肿瘤） like prostate（前列腺） cancer.

Experiments Yield Surprising Results

The researchers conducted a series of experiments in tumor cell lines and mouse models that have shed new light on the interplay（相互影响） of Skp2 and cellular senescence.

"We discovered that Skp2 actually exhibits oncogenic activity, which is required for cancer development in multiple tumor models, such as the Pten-deficient and the p19Arf -deficient mouse models," Lin said. "We found that Skp2 regulates tumorigenesis（肿瘤发生） to trigger the cellular senescence program. This program is unexpectedly independent of the p19Arf-p53 pathway, which was previously⁸ believed to be critical for cellular senescence."

The researchers also found that induction⁹ of cellular senescence did not cause DNA¹⁰ damage, and their results suggest that Skp2 inactivation¹¹ can suppress cellular transformation¹² to cancer even in the setting of an impaired¹³（受损的） p19Arf-p53 senescence response.

Moreover, research conducted in mouse models with faulty or inactive tumor suppressor networks showed that Skp2 deficiency and oncogenic signaling elicit¹⁴ a senescence response that restricts formation of tumors.

Novel Findings Point to New Therapeutic¹⁵ Approaches

Lin said these studies suggest that in the future Skp2 might be an effective therapeutic（治疗的） target for tumors with deregulated Akt signaling due to the loss or inactivation of Pten functions. Pten, which is commonly lost in human cancers, acts as a tumor suppressor gene by suppressing Akt signaling. Skp2 and Pten loss are believed to cooperate in triggering cellular senescence to restrict invasive prostate cancer.

"We now want to examine whether Skp2 is required in other tumor model systems, such as a HER2 model, to determine whether it is globally required for an oncogenic（致瘤的，瘤原性的） event," said Lin, who previously was affiliated¹⁶ with（交往，参加） Memorial Sloan-Kettering Cancer Center's Department of Pathology and Cancer Biology and Genetics program and continued his research at M. D. Anderson. "We are testing whether Skp2 might be widely used for different types of cancer or perhaps used to trigger this newly described cellular senescence program."

The researchers also are working to develop a Skp2-specific small molecule¹⁷ inhibitor（抑制剂） to establish that the protein is indeed an important therapeutic target in cancer treatment. They believe that Skp2-based therapy might also be used as a general cancer treatment that could be combined with existing cancer therapies.