A unique amidoanthraquinone derivative displays antiproliferative activity against human hormone-refractory metastatic prostate cancers through activation of LKB1-AMPK-mTOR signaling pathway

Abstract

Hormone-refractory metastatic prostate cancer (HRMPC), which is metastatic and resistant to hormone therapy, is an intractable problem in clinical treatment. Anthraquinone-based natural products and synthetic compounds have shown anticancer activity. However, cardiac toxicity is a major adverse reaction in these compounds. CC-36, a unique anthraquinone derivative, displayed higher antiproliferative activity in HRMPC than that in H9c2 cardiomyoblasts and normal prostate cells with the selectivity of five and twelve times, respectively. CC-36 caused G1 arrest of the cell cycle associated with an upregulation of p21 and downregulated levels of cyclin D1 and cyclin E expressions. Immunoprecipitation assay and Western blotting analysis showed that CC-36 triggered an increase of TSC1/TSC2 association and suppressed the phosphorylation of mammalian target of rapamycin (mTOR) (Ser2448) and p70 ribosomal protein S6 kinase (p70S6K) (Thr389), indicating the inhibition of both kinases' activities. CC-36 induced liver kinase B1 (LKB1) phosphorylation at Thr189, leading to LKB1 translocation from nucleus to cytosol for AMPKα phosphorylation (Thr172) and the kinase activation. The signaling pathway was validated using small interfering RNA (siRNA) technique with LKB1 knockdown. The combination treatment of MK2206 (a specific Akt inhibitor) with CC-36 showed a synergistic apoptosis in PC-3 cells indicating a potential combination strategy for LKB1 activators. Taken together, the data suggest that CC-36 displays anti-HRMPC activity through the activation of LKB1-AMPK pathway, leading to an inhibition of mTOR signaling and the induction of G1 arrest of the cell cycle. The combination use of Akt inhibitors with agents acting through LKB1-AMPK-mTOR pathway is a potential strategy for HRMPC treatment.

Cytochrome P450 17A1 inhibitor abiraterone attenuates cellular growth of prostate cancer cells independently from androgen receptor signaling by modulation of oncogenic and apoptotic pathways

“…Increased DNA fragmentation as determined by TUNEL assay, as well as downregulation of the cell survival factor survivin and elevated levels of the cell cycle inhibitor p21 and the effector caspase-3 clearly indicated an execution of apoptotic mechanisms. These data confirm former studies which have shown that anticancer drugs affect the biosynthesis of these intrinsic apoptotic factors in PC-3 cells (28,(30)(31)(32). Surprisingly, our results could not be definitely verified by Annexin V staining.…”

n-3 polyunsaturated fatty acids abrogate mTORC1/2 signaling and inhibit adrenocortical carcinoma growth in vitro and in vivo

“…Our results at least showed that n-6 PUFAs may be related to ACC growth and upregulation of mTOR signaling in ACC may be partly due to AA uptake. It has been reported that prostate or breast-specific knockout of TSC1 (which activates mTORC1) can lead to prostate or breast carcinogenesis (28,29). Therefore, we can use the adrenal cortical-specific Cre mouse and TSC1loxp mouse to investigate whether adrenal mTORC1 activation could lead to adrenal hyperplasia, adenoma formation or ACC development and confirm the role of mTORC1 in adrenal carcinogenesis (30).…”

Lower AMP-activated protein kinase level is associated with the vulnerability of coronary atherosclerotic plaques by attenuating the expression of monocyte autophagy

“…Activation of AMPK and inhibition of mTOR promote multiple steps of autophagosome formation. Recent studies have shown that AMPK induced phosphorylation of Ulk1 [24,25]. A balance between mTORC1 and AMPK may regulate Ulk1 activity and subsequent autophagy initiation.…”