* Inhibition of CAMKK2 impairs autophagy and castration-resistant prostate cancer via suppression of AMPK-ULK1 signaling.
- Previous work has suggested androgen receptor (AR) signaling mediates prostate cancer progression in part through the modulation of autophagy. However, clinical trials testing autophagy inhibition using chloroquine derivatives in men with castration-resistant prostate cancer (CRPC) have yet to yield promising results, potentially due to the side effects of this class of compounds. We hypothesized that identification of the upstream activators of autophagy in prostate cancer could highlight alternative, context-dependent targets for blocking this important cellular process during disease progression. Here, we used molecular, genetic, and pharmacological approaches to elucidate an AR-mediated autophagy cascade involving Ca2+/calmodulin-dependent protein kinase kinase 2 (CAMKK2; a kinase with a restricted expression profile), 5'-AMP-activated protein kinase (AMPK), and Unc-51 like autophagy activating kinase 1 (ULK1), but independent of canonical mechanistic target of rapamycin (mTOR) activity. Increased CAMKK2-AMPK-ULK1 signaling correlated with disease progression in genetic mouse models and patient tumor samples. Importantly, CAMKK2 disruption impaired tumor growth and prolonged survival in multiple CRPC preclinical mouse models. Similarly, an inhibitor of AMPK-ULK1 blocked autophagy, cell growth, and colony formation in prostate cancer cells. Collectively, our findings converge to demonstrate that AR can co-opt the CAMKK2-AMPK-ULK1 signaling cascade to promote prostate cancer by increasing autophagy. Thus, this pathway may represent an alternative autophagic target in CRPC.
=>茂み, 成長, 増加, 発展, 栽培, 腫よう, 成長物
Overview of noun growth
The noun growth has 7 senses (first 5 from tagged texts)
1. (37) growth, growing, maturation, development, ontogeny, ontogenesis -- ((biology) the process of
an individual organism growing organically; a purely biological unfolding of events involved in an
organism changing gradually from a simple to a more complex level; "he proposed an indicator of
osseous development in children")
2. (20) growth -- (a progression from simpler to more complex forms; "the growth of culture")
3. (3) increase, increment, growth -- (a process of becoming larger or longer or more numerous or
more important; "the increase in unemployment"; "the growth of population")
4. (3) growth -- (vegetation that has grown; "a growth of trees"; "the only growth was some salt
grass")
5. (1) emergence, outgrowth, growth -- (the gradual beginning or coming forth; "figurines presage
the emergence of sculpture in Greece")
6. growth -- ((pathology) an abnormal proliferation of tissue (as in a tumor))
7. growth -- (something grown or growing; "a growth of hair")
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