Cacalol, a natural sesquiterpene, induces apoptosis in breast cancer cells by modulating Akt-SREBP-FAS signaling pathway

Abstract

We previously isolated cacalol as a free radical-scavenging compound from Cacalia delphiniifolia which is a traditional Asian herbal plant and is believed to have medicinal effects on cancer. In this report, we demonstrated that cacalol has strong anti-proliferation effect on breast cancer cells and induces apoptosis by activating a pro-apoptotic pathway. We also found that a combination of cacalol and other chemotherapeutic drugs (Taxol and cyclophosphamide) synergistically induced apoptosis and partially overcame chemo-resistance. To further gain a mechanistic insight, we tested a potential inhibitory effect of cacalol on fatty acid synthase gene (FAS) in breast cancer cells, and found that cacalol significantly modulated the expression of the FAS gene, which resulted in apoptosis through activation of DAPK2 and caspase 3. We have also shown that cacalol significantly suppressed the Akt-sterol regulatory element-binding proteins (SREBP) signaling pathway and concomitant transcriptional activation of FAS. In a xenograft model of nude mouse, when cacalol was administered intraperitoneally, tumor growth was significantly suppressed. Importantly, oral administration of cacalol before implanting tumors showed significant preventive effect on tumor growth in the same animal model. Furthermore, the treatment of mice with a combination of low dose of Taxol and cacalol significantly suppressed the tumor growth. Taken together, our results indicate that cacalol induces apoptosis in breast cancer cells and impairs mammary tumor growth in vivo by blocking the expression of the FAS gene through modulation of Akt-SREBP pathway, suggesting that cacalol has potential utility as a chemopreventive and chemotherapeutic agent for breast cancer.

Anti-Cancer Drugs Targeting Fatty Acid Synthase (FAS)

“…They synergistically induced apoptosis, partially overcame chemo-resistance and significantly suppressed tumor growth in vivo. These results indicate that inhibition of FAS potentially overcome hypoxia-induced chemo-resistance in tumor cells, and strongly support an idea to use cacalol as a dietary supplement for chemopreventive and chemotherapeutic adjuvant for breast cancer [109].…”

“…Cacalol was shown to significantly inhibit the expression of FAS at mRNA and protein levels, which resulted in significant apoptosis in breast cancer cells MDA-MB231 and MCF7, but not in normal breast epithelial cells (HMEC). The treatment of tumor cells with cacalol induced DAPK2 and caspase-3, while specific inhibitors such as TOFA and fumonisin B1 significantly blocked the ability of cacalol to induce apoptosis [109]. Therefore, cacalol-induced apoptosis is considered to be a direct consequence of the inhibitory effect of cacalol on FAS.…”

“…We have recently found a dietary phytochemical sesquiterpene derivative (C 15 H 18 O 2 ), Cacalol, as a novel and potent FAS inhibitor [109]. Cacalol has been isolated from various medicinal plants including Chinese herbs Ligularia tsangchanensis and Roldana angulifolia as well as Psacalium.…”

Elevated lipogenesis in epithelial stem-like cell confers survival advantage in ductal carcinoma in situ of breast cancer

“…Elevated level of lipogenic enzymes and upregulation of lipogenesis is a hallmark of cancer and blocking the lipogenic pathway is known to cause tumor cell death by apoptosis. 5,[10][11][12][13] These observations suggest that upregulation of lipogenic genes is not merely a consequence but that it has a critical role in tumor initiation, possibly by providing the source for membrane biosynthesis and metabolic energy through b-oxidation. [24][25][26][27][28] Our analysis of existing clinical cohort data of DCIS patients and IHC staining of tumor samples clearly indicates that all key lipogenic genes and their master regulator, SREBP1, are significantly upregulated at relatively early stages of DCIS, and this coordinated upregulation of lipogenic genes is also observed in CSCs of DCIS.…”

“…8 Interestingly, inhibition of lipogenic enzymes blocks cell proliferation, induces apoptosis of cancer cells and retards the growth of human tumors in mouse xenograft models in vivo. [9][10][11][12][13] These findings suggest that the role of lipogenesis in cancers may extend beyond bulk membrane biosynthesis to meet the demand of rapid cell proliferation. According to the recent cancer stem cell theory, which still remains a hypothesis, tumors develop from a small population of cancer stem-like cells (CSCs) that have a strong tumor-initiating ability.…”