Anisomycin inhibits angiogenesis, growth, and survival of triple-negative breast cancer through mitochondrial dysfunction, AMPK activation, and mTOR inhibition

Abstract

Aberrant upregulation of mitochondrial biogenesis is observed in breast cancer and holds potential therapeutic option. In our work, we showed that inhibition of mitochondrial function by anisomycin is effective against triple-negative breast cancer (TNBC). Anisomycin inhibits growth and induces caspase-dependent apoptosis in a panel of TNBC cell lines. Of note, anisomycin at a tolerable dose remarkably suppresses growth of TNBC in mice. In addition, anisomycin effectively targets breast cancer angiogenesis through inhibiting capillary network formation, migration, proliferation, and survival. Mechanistic studies show that although anisomycin activates p38 and JNK, their activations are not required for anisomycin's action. In contrast, anisomycin inhibits mitochondrial respiration, and decreases mitochondrial membrane potential and adenosine triphosphate (ATP) level. The inhibitory effect of anisomycin is significantly reversed in mitochondria respiration-deficient ρ0 cells. As a consequence, anisomycin activates AMPK and inhibits mammalian target-of-rapamycin signaling pathways. Our work demonstrated that anisomycin is a useful addition to the treatment armamentarium for TNBC.

AaLaeA targets AaFla1 to mediate the production of antitumor compound in Alternaria alstroemeria

“…Some compounds with antitumor activity were found to be significantly upregulated (Table 3). Quercetin [32], strychnopentamine [33], gitogenin [34], rhodioloside [35], liensinine [36], l ‐selenomethionine [37], compactin [38], tonantzitlolone b [39], ginsenoside rg2 [40], campesterol [41], pristimerin derivative [42], cinobufagin [43], and anisomycin [44] have been shown to have antitumor activity. Among them, quercetin, a flavonoid, was the most significantly upregulated.…”

“…In contrast, overexpression of Fla1 caused a significant increment in the antitumor activity of the strain, with a reduction in IC 50 from 445 μg/mL to 368 μg/mL and a significant 7‐fold increment in apoptosis. Antitumor‐related compounds have been reported to accumulate in Fla1 overexpressing transformants, for example, quercetin [32], strychnopentamine [33], gitogenin [34], rhodioloside [35], liensinine [36], l ‐selenomethionine [37], compactin [38], tonantzitlolone b [39], ginsenoside rg2 [40], campesterol [41], pristimerin derivative [42], cinobufagin [43] and anisomycin [44], with the flavonoid quercetin being the most significantly upregulated. This result is in contrast to the significant reduction in flavonoid content of AaLaeA OE26 , which also confirms in terms of compound accumulation that AaFla1 is negatively regulated by AaLaeA, and therefore affecting the antitumor activity of the strain.…”

Novel Anti-Cancer Products Targeting AMPK: Natural Herbal Medicine against Breast Cancer

“…Moreover, lovastatin-induced activation of LKB1/AMPK increased the expression of p21 and decreased the level of survivin via phosphorylating p38 and p53 [ 260 ]. In addition to the modulators described above, vitamin D3, and anisomycin (isolated from Streptomyces griseolus ) are also regarded as activators of AMPK [ 261 , 262 ].…”

AaLaeA targets AaFla1 to mediate the production of antitumor compound in Alternaria alstroemeria

“…Some compounds with anti-tumor activity were found to be significantly up-regulated (Table 3). Quercetin [26], Strychnopentamine [27], Gitogenin [28], Rhodioloside [29], Liensinine [30], L-Selenomethionine [31], Compactin [32], Tonantzitlolone B [33], Ginsenoside Rg2 [34], Campesterol [35], Pristimerin derivative [36], Cinobufagin [37] and Anisomycin [38] have been shown to have antitumour activity. Among them, quercetin, a flavonoid, was the most significantly up-regulated.…”