4.7 Review

Impact of alternative splicing on mechanisms of resistance to anticancer drugs

Journal

BIOCHEMICAL PHARMACOLOGY
Volume 193, Issue -, Pages -

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2021.114810

Keywords

Alternative splicing; Chemoresistance; Chemotherapy; Pharmacoresistance; Tumor; Spliceosome

Funding

  1. CIBERehd [EHD15PI05/2016]
  2. Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain [PI16/00598, PI19/00819]
  3. European Regional Development Fund/European Social Fund, Investing in your future
  4. Spanish Ministry of Economy, Industry and Competitiveness [SAF201675197-R, SAF2017-88457-R, AGL2017-85270-R]
  5. Junta de Castilla y Leon [SA063P17]
  6. Junta de Andalucia [CTS235, CTS164]
  7. AECC Scientific Foundation, Spain
  8. University of Salamanca [18.K137/463AC01, 18. K140/463AC01]
  9. Centro Internacional sobre el Envejecimiento (OLDHEPAMARKER), Spain [0348_CIE_6_E]
  10. Fundacion University of Salamanca, Spain [PC-TCUE18-20_051]
  11. Fundacio Marato TV3 [201916-31]
  12. Ministry of Science, Innovation and Universities, Spain

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Many tumors exhibit resistance to anticancer drugs, which can be intrinsic or acquired and involve multiple mechanisms. The resistance is based on the dynamic expression of over a hundred genes, forming the so-called "resistome." Splicing variants reduce the efficacy of anticancer drugs by altering molecular targets, enhancing DNA repair ability, and changing the balance between survival and apoptosis signals.
A shared characteristic of many tumors is the lack of response to anticancer drugs. Multiple mechanisms of pharmacoresistance (MPRs) are involved in permitting cancer cells to overcome the effect of these agents. Pharmacoresistance can be primary (intrinsic) or secondary (acquired), i.e., triggered or enhanced in response to the treatment. Moreover, MPRs usually result in the lack of sensitivity to several agents, which accounts for diverse multidrug-resistant (MDR) phenotypes. MPRs are based on the dynamic expression of more than one hundred genes, constituting the so-called resistome. Alternative splicing (AS) during pre-mRNA maturation results in changes affecting proteins involved in the resistome. The resulting splicing variants (SVs) reduce the efficacy of anticancer drugs by lowering the intracellular levels of active agents, altering molecular targets, enhancing both DNA repair ability and defensive mechanism of tumors, inducing changes in the balance between pro-survival and pro-apoptosis signals, modifying interactions with the tumor microenvironment, and favoring malignant phenotypic transitions. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the impact of AS on MPR in cancer cells.

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