Search

Background and Aims: Synthetic cyclin-dependent kinase (CDK) 4/6 inhibitors exert antitumor effects by forcing RB1 in unphosphorylated status, causing not only cell cycle arrest but also cellular senescence, apoptosis, and increased immunogenicity. These agents currently have an indication in advanced breast cancers and are in clinical trials for many other solid tumors. HCC is one of promising targets of CDK4/6 inhibitors. RB family dysfunction is often associated with the initiation of HCC; however, this is revivable, as RB family members are not frequently mutated or deleted in this malignancy. Approach and Results: Loss of all Rb family members in transformation related protein 53 (Trp53)−/− mouse liver resulted in liver tumor reminiscent of human HCC, and re-expression of RB1 sensitized these tumors to a CDK4/6 inhibitor, palbociclib. Introduction of an unphosphorylatable form of RB1 (RB7LP) into multiple liver tumor cell lines induced effects similar to palbociclib. By screening for compounds that enhance the efficacy of RB7LP, we identified an I kappa B kinase (IKK)β inhibitor Bay 11-7082. Consistently, RB7LP expression and treatment with palbociclib enhanced IKKα/β phosphorylation and NF-κB activation. Combination therapy using palbociclib with Bay 11-7082 was significantly more effective in hepatoblastoma and HCC treatment than single administration. Moreover, blockade of IKK–NF-κB or AKT pathway enhanced effects of palbociclib on RB1-intact KRAS Kirsten rat sarcoma viral oncogene homolog mutated lung and colon cancers. Conclusions: In conclusion, CDK4/6 inhibitors have a potential to treat a wide variety of RB1-intact cancers including HCC when combined with an appropriate kinase inhibitor. Refereed/Peer-reviewed

RB1 gene is often homozygously deleted or mutated in prostate adenocarcinomas following acquirement of castration resistance and/or metastatic ability. We found that SUCLA2 gene is frequently involved in the deletion of the RB1 gene region in advanced prostate cancer. SUCLA2 constitutes the β-subunit of succinate CoA ligase heterodimer that reversibly converts succinyl CoA into succinate. We sought the possibility that deletion of SUCLA2 gives rise to a metabolic vulnerability that could be targeted therapeutically. We found a significant metabolic shift in SUCLA2-deleted prostate cancer cells, including lower mitochondrial respiratory activity. By screening a number of libraries for compounds that induce cell death selectively in SUCLA2-deficient prostate cancer cells, we identified thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone) and PMA (phorbol-12-myristate-13-acetate) from a natural compound library. These findings indicate that the metabolic vulnerability in SUCLA2-deficient prostate cancer cells is pharmacologically targetable. Refereed/Peer-reviewed

Dietary fat consumption during accelerated stages of mammary gland development, such as peripubertal maturation or pregnancy, is known to increase the risk for breast cancer. However, the underlying molecular mechanisms are not fully understood. Here we examined the gene expression profile of mouse mammary epithelial cells (MMECs) on exposure to a high‐fat diet (HFD) or control diet (CD). Trp53 −/− female mice were fed with the experimental diets for 5 weeks during the peripubertal period (3‐8 weeks of age). The treatment showed no significant difference in body weight between the HFD‐fed mice and CD‐fed mice. However, gene set enrichment analysis predicted a significant enrichment of c‐Myc target genes in animals fed HFD. Furthermore, we detected enhanced activity and stabilization of c‐Myc protein in MMECs exposed to a HFD. This was accompanied by augmented c‐Myc phosphorylation at S62 with a concomitant increase in ERK phosphorylation. Moreover, MMECs derived from HFD‐fed Trp53 −/− mouse showed increased colony‐ and sphere‐forming potential that was dependent on c‐Myc. Further, oleic acid, a major fatty acid constituent of the HFD, and TAK‐875, an agonist to G protein‐coupled receptor 40 (a receptor for oleic acid), enhanced c‐Myc stabilization and MMEC proliferation. Overall, our data indicate that HFD influences MMECs by stabilizing an oncoprotein, pointing to a novel mechanism underlying dietary fat‐mediated mammary carcinogenesis., We analyzed mammary gland epithelial cells derived from Trp53 −/− mice fed a high‐fat diet. This revealed a possibility that fatty acids induce stabilization of c‐Myc in mammary gland epithelial cells through enhancement of mitogenic signaling.