Editors' ChoiceCancer

Unsplicing senescence

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Science Translational Medicine  08 Aug 2018:
Vol. 10, Issue 453, eaau7386
DOI: 10.1126/scitranslmed.aau7386


The secretion of protumorigenic factors by senescent cells is controlled by alternative splicing and can be targeted in cancer.

Cellular senescence is an antiproliferative program that restricts the propagation of cells under stress. Senescent cells are characterized in part by the secretion of factors collectively known as the senescence-associated secretory phenotype (SASP). The main outputs of senescence are beneficial as senescence imposes a potent barrier to tumorigenesis and contributes to tissue repair and embryonic development. However, senescence can also have detrimental consequences as the SASP can enhance proliferation of neighboring tumor cells, chemoresistance, and aging. In the last few years, there has been a growing interest in finding therapeutic strategies that can repress the negative effects of senescence while maintaining or even promoting the positive aspects. In a recent study, Georgilis et al. have shown that PTBP1, a regulator of alternative splicing, can control the SASP factors involved in the protumorigenic effects of senescence, providing a potential therapeutic target for cancer treatment.

In an effort to identify drug targets that control the protumorigenic effects of senescence, the authors performed a high-content siRNA (small interfering RNA) screen and focused on those siRNAs that repressed the pro-inflammatory SASP without reverting the senescence cell cycle arrest. PTBP1, a splicing regulator, was the strongest candidate. Additional experiments demonstrated that PTBP1 inhibition in senescent cells was able to reduce the proliferation of neighboring malignant cells. PTBP1 repression also reduced senescence-associated immune surveillance, considered to be one of the desirable outcomes of SASP and senescence, but surprisingly did not affect subsequent tumor development. This finding suggested that PTBP1 inhibition may only impact the deleterious activities of senescent cells. Mechanistically, PTBP1 regulated the alternative splicing of several genes, such as EXOC7, which are direct regulators of SASP. Future studies will need to elucidate whether PTBP1 inhibition can help reduce other harmful effects of senescence, including aging and resistance to therapy. It will also be critical to further interrogate whether inhibiting PTBP1 can affect tissue repair or embryonic development to better devise the most appropriate settings for this novel therapeutic strategy.

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