Feedback regulation of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 via ATM/Chk2 pathway contributes to the resistance of MCF-7 breast cancer cells to cisplatin

Abstract

The methyl methanesulfonate and ultraviolet-sensitive gene clone 81 protein is a structure-specific nuclease that plays important roles in DNA replication and repair. Knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 has been found to sensitize cancer cells to chemotherapy. However, the underlying molecular mechanism is not well understood. We found that methyl methanesulfonate and ultraviolet-sensitive gene clone 81 was upregulated and the ATM/Chk2 pathway was activated at the same time when MCF-7 cells were treated with cisplatin. By using lentivirus targeting methyl methanesulfonate and ultraviolet-sensitive gene clone 81 gene, we showed that knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 enhanced cell apoptosis and inhibited cell proliferation in MCF-7 cells under cisplatin treatment. Abrogation of ATM/Chk2 pathway inhibited cell viability in MCF-7 cells in response to cisplatin. Importantly, we revealed that ATM/Chk2 was required for the upregulation of methyl methanesulfonate and ultraviolet-sensitive gene clone 81, and knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 resulted in inactivation of ATM/Chk2 pathway in response to cisplatin. Meanwhile, knockdown of methyl methanesulfonate and ultraviolet-sensitive gene clone 81 activated the p53/Bcl-2 pathway in response to cisplatin. These data suggest that the ATM/Chk2 may promote the repair of DNA damage caused by cisplatin by sustaining methyl methanesulfonate and ultraviolet-sensitive gene clone 81, and the double-strand breaks generated by methyl methanesulfonate and ultravioletsensitive gene clone 81 may activate the ATM/Chk2 pathway in turn, which provide a novel mechanism of how methyl methanesulfonate and ultraviolet-sensitive gene clone 81 modulates DNA damage response and repair.

Expression of MUS81 Mediates the Sensitivity of Castration-Resistant Prostate Cancer to Olaparib

“…Interestingly, previous research attested that the ATM protein level in prostate cancer cells was elevated compared to heathy samples [ 33 ], and activation of ATM in prostate intraepithelial neoplasia (PIN) was recognized as a precursor of prostate cancer [ 34 ]. MUS81 silencing inactivated ATM/Chk2, thereby enhancing the sensitivity of breast cancer cell MCF-7 to cisplatin [ 17 ]. We studied the relationship between the expressions of MUS81, ATM, and p-ATM in transfected cells.…”

“…McPherson et al [12] attested that the death of 73% MUS81 -/mice and 50% of MUS81 +/mice was due to diverse spontaneous tumors, e.g., breast cancer, lymphoma, and PCa, suggesting that MUS81 may function as an effective tumor suppressor in mice. Some researchers have found that the expression of MUS81 is downregulated in human hepatocellular carcinoma, gastric cancer, and colorectal cancer [13][14][15], and its SNP links to increased risks of breast cancer [16], but its expression was upregulated in ovarian cancer tissues [17][18][19]. Despite such research indicating differential expression of MUS81 in different human tissues and potential roles in malignant tumors, its expressions and roles in CRPC remain to be determined.…”

ILP-2: A New Bane and Therapeutic Target for Human Cancers

“…IAPs seem to have a feedback effect whereby a single protein can achieve the same purpose through different biochemical mechanisms ( 82 ). Although we know that most studies on ILP-2 have focused on its role as a caspase inhibitor, there is growing evidence that it also achieves this through other mechanisms ( 83 ).…”

Regulation of Structure-Specific Endonucleases in Replication Stress

“…Although Cds1-Mus81 S.p. interaction is conserved in human cells (CHK2-MUS81), it is unclear if CHK2 directly regulates MUS81 as in fission yeast (reviewed in [8]), although there is evidence that CHK2 up-regulates the protein level of MUS81; MUS81 in turn contributes to activation of CHK2 in Cisplatin-treated breast cancer cells (Figure 3) [84].…”

“…It is unclear whether MUS81 is directly regulated by these checkpoint kinases in human cells. However, there is evidence that CHK2 upregulates MUS81 protein levels and MUS81 in turn contributes to CHK2 activation upon DNA damage (indicated by dashed double-headed arrow) [84]. Deleterious MUS81-dependent processing of replication intermediates following CHK1 inhibition suggests that CHK1 downregulates MUS81 activity (indicated by dashed red line) [68,69,70].…”