Despite its potent antitumor effect, clinical use of Doxorubicin is limited because of serious side effects including myocardial toxicity. Understanding the cellular mechanism involved in this process in a better manner is beneficial for optimizing Doxorubicin treatment. In the current study, the authors focus on the AMP-activated protein kinase (AMPK) in the said process. In this study, the authors discovered for the first time that Doxorubicin induces AMPK activation in cultured rat embryonic ventricular myocardial H9c2 cells. Reactive oxygen species (ROS)-dependent LKB1 activation serves as the upstream signal for AMPK activation by Doxorubicin. Evidence in support of the activation of AMPK contributing to Doxorubicin-induced H9c2 cell death/apoptosis--probably by modulating multiple downstream signal targets, including regulating JNK, p53, and inhibiting mTORC1--is provided in this article.

The molecular basis for induction of apoptosis in melanoma cells by vincristine remains unknown. Here we tested the potential involvement of AMP-activated protein kinase (AMPK) in this process. We found for the first time that vincristine induces AMPK activation (AMPKα, Thr 172) and Acetyl-CoA carboxylase (ACC, Ser 79) (a downstream molecular target of AMPK) phosphorylation in cultured melanoma cells in vitro. Reactive oxygen species (ROS) dependent LKB1 activation serves as the upstream signal for AMPK activation. AMPK inhibitor (compound C) or AMPKα siRNA knockdown inhibits vincristine induced B16 melanoma cell apoptosis, while AMPK activator 5-aminoimidazole-4-carboxamide-1-β-riboside (AICAR) enhances it. AMPK activation is involved in vincristine induced p53 phosphorylation and stabilization, the latter is known to mediate melanoma cell apoptosis. Further, activation of AMPK by vincristine inhibits mTOR Complex 1 (mTORC1) in B16 melanoma cells, which serves as another important mechanism to induce melanoma cell apoptosis. Our study provides new insights into understanding the cellular and molecular mechanisms of vincristine induced cancer cell death/apoptosis. We suggest that combining AMPK activator AICAR with vincristine may have potential to be used as a new therapeutic intervention against melanoma.

Note: The sample collection time in parentheses in the column heads is the month after osimertinib treatment. Em dash indicates that the mutation was undetectable. a Coverage depth of EGFR in patient's tumor or cell-free DNA samples normalized to the value in patient's own whole blood control sample. FFPE, formalin-fixed paraffin-embedded.

No abstract

Published data on the association between lymphocyte-specific protein 1 (LSP1) rs3817198T>C polymorphism and breast cancer risk are inconclusive. Hence, we conducted a meta-analysis of the LSP1 gene and risk of breast cancer to obtain the most reliable estimate of the association. PubMed, Embase and Web of Science databases were searched. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were extracted and pooled to assess the strength of the association between the LSP1 rs3817198T>C polymorphism and risk of breast cancer. A total of seven eligible studies including 33,920 cases and 35,671 controls based on the search criteria were involved in this meta-analysis. The distributions of genotypes in the controls were all in agreement with Hardy-Weinberg equilibrium. We observed that the LSP1 rs3817198T>C polymorphism was significantly correlated with breast cancer risk when all studies were pooled into the meta-analysis (the allele contrast model: OR = 1.06, 95% CI = 1.04-1.08; the homozygote codominant: OR = 1.14, 95% CI = 1.01-1.28). In the stratified analysis by ethnicity, significant association was observed in Caucasians for CC versus TT homozygote codominant model (OR = 1.25; 95% CI = 1.03-1.52) and for the recessive model (OR = 1.22; 95% CI = 1.02-1.47). There was significant association observed in Africans for CC versus TT homozygote codominant model (OR = 0.45; 95% CI = 0.22-0.92) and for the recessive model (OR = 0.43; 95% CI=0.22-0.88). Also, significant association was observed in mixed ethnicities for CC versus TT homozygote codominant model (OR = 1.12; 95% CI = 1.05-1.19). When stratified by study design, statistically significantly elevated risk was found in nested case-control studies (CC vs. TT: OR = 1.12, 95% CI = 1.05-1.19). But no significant association was observed for all comparison models between LSP1 rs3817198T>C polymorphism and breast cancer risk in hospital-based and people-based studies. When stratified by BRCA1 mutation carriers status, statistically significantly elevated risk was found in this meta-analysis (the allele contrast model: OR = 1.07, 95% CI = 1.01-1.14; the dominant model: OR = 1.09, 95% CI = 1.00-1.18). And significant association was found in the BRCA2 mutation carriers in the allele contrast (OR = 1.11, 95% CI = 1.03-1.20), the homozygote codominant (OR = 1.23, 95% CI = 1.04-1.47), the heterozygote codominant (OR = 1.12, 95% CI = 1.00-1.25) and the dominant models (OR = 1.14, 95% CI = 1.03-1.27). There was significant association between LSP1 rs3817198T>C polymorphism and breast cancer risk in BRCA1 and BRCA2 positive cohort in all comparison models (the allele contrast model: OR = 1.08, 95% CI = 1.03-1.13; CC vs. TT: OR = 1.16, 95% CI = 1.05-1.29; TC vs. TT: OR = 1.09, 95% CI = 1.01-1.16; the dominant model: OR = 1.10, 95% CI = 1.03-1.17; the recessive model: OR = 1.12, 95% CI = 1.01-1.23). In conclusion, this meta-analysis suggests that the LSP1 rs3817198T>C polymorphism is a low-penetrant risk factor for developing breast cancer but may not be in Africans.