Recent advances of SIRT1 and implications in chemotherapeutics resistance in cancer

Abstract

Cancer is a big group of diseases and one of the leading causes of mortality worldwide. Despite enormous studies and efforts are being carried out in understanding the cancer and developing drugs against tumorigenesis, drug resistance is the main obstacle in cancer treatments. Chemotherapeutic treatment is an important part of cancer treatment and drug resistance is getting gradually multidimensional with the advancement of studies in cancer. The underlying mechanisms of drug resistance are largely unknown. Sirtuin1 (SIRT1) is a type of the Class III histone deacetylase family that is distinctively dependent on nicotinamide adenine dinucleotide (NAD+) for catalysis reaction. SIRT1 is a molecule which upon upregulation directly influences tumor progression, metastasis, tumor cell apoptosis, autophagy, DNA repair, as well as other interlinked tumorigenesis mechanism. It is involved in drug metabolism, apoptosis, DNA damage, DNA repair, and autophagy, which are key hallmarks of drug resistance and may contribute to multidrug resistance. Thus, understanding the role of SIRT1 in drug resistance could be important. This study focuses on the SIRT1 based mechanisms that might be a potential underlying approach in the development of cancer drug resistance and could be a potential target for drug development.

Keywords: DNA damage repair; SIRT1; chemotherapeutics resistance; tumorigenesis.

Figure 1

General mechanism of chemoresistance by SIRT1. Drug absorption, circulation, and abolition in cancer cells, SIRT1 regulates drug mechanism to activation of DNA damage repair machinery and downregulate DNA damage and apoptosis pathway through promoting multidrug resistance and cell proliferation.

Figure 2

SIRT1 pathway overview in chemoresistance cancer. SIRT1 is an NAD+-dependent histone deacetylase protein that modulates several pathways of chemoresistance cancer. Overexpression of SIRT1 promotes DNA damage repair, antiapoptotic effects, confer cell proliferation and increases the function of chemoresistance in cells via protein regulators such as activators or inhibitors of SIRT1 have been described. The downstream activity targets deacetylation such as cellular metabolism, senescence, DNA repair and modulates the tumor microenvironment through multiple cell signaling pathways.

Figure 3

SIRT1 role in cancer development and cell progression, invasion, metastasis and MDR. SIRT1 activates many pathways in tumorigenesis such as cancer progression, cell invasion and migration, metastasis and chemoresistance. SIRT1 overexpression subjected to regulate multiple pathways of cancer including metastatic cascade and invasion, tumor suppression and cell proliferation, enhances the stemness and modulates the tumor microenvironment for multidrug resistance in cancer. Given all recent data discussed in above study about potential of SIRT1 to promote multidrug resistance mechanism and tumorigenesis has been summarized in this figure.