AMP-activated protein kinase promotes human prostate cancer cell growth and survival

Abstract

The molecular mechanisms underlying the development and progression of prostate cancer are poorly understood. AMP-activated protein kinase (AMPK) is a serine-threonine kinase that is activated in response to the hypoxic conditions found in human prostate cancers. In response to energy depletion, AMPK activation promotes metabolic changes to maintain cell proliferation and survival. Here, we report prevalent activation of AMPK in human prostate cancers and provide evidence that inhibition or depletion of AMPK leads to decreased cell proliferation and increased cell death. AMPK was highly activated in 40% of human prostate cancer specimens examined. Endogenous AMPK was active in both the androgensensitive LNCaP cells and the androgen-independent CWR22Rv1 human prostate cancer cells. Depletion of AMPK catalytic subunits by small interfering RNA or inhibition of AMPK activity with a small-molecule AMPK inhibitor (compound C) suppresses human prostate cancer cell proliferation. Apoptotic cell death was induced in LNCaP and CWR22Rv1 cells at compound C concentrations that inhibited AMPK activity. The evidence provided here is the first report that the activated AMPK pathway is involved in the growth and survival of human prostate cancer and offers novel potential targets for chemoprevention of human prostate cancer. [Mol Cancer Ther 2009;8(4):733-41]

Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis

“…For instance, AMPK activation correlated with survival and Cdk2 activation in Tsc2-deficient cells (Short et al, 2008), and with proliferation and survival of prostate cancer cells (Park et al, 2009). Furthermore, Liang et al (2007) recently linked activation of AMPK to p27-mediated autophagy-based cell survival under metabolic stress, a mechanism that may be associated with the development of solid tumors under low supply of nutrients and oxygen.…”

Adenosine Inhibits Tumor Cell Invasion via Receptor-Independent Mechanisms

“…In particular, the malignant human prostate tissue was shown to display a higher AMPK activity than normal tissue cells. In addition, the downregulation of AMPK in prostate cancer cell lines, but not in nontumorigenic prostate epithelial cells, reduced cell proliferation and induced apoptosis (30,31). These conflicting results presumably depend on the tumor type and may also reflect a fine-tuned biphasic regulation of AMPK function and/or changing role of AMPK at different disease states.…”

“…However, the mechanisms of these acute effects may differ substantially from the chronic effects of adenosine on AMPK inhibition seen in our experimental settings. In addition, the modulation of AMPK in normal and transformed cells often triggers the opposing effects due to differential deletion of downstream tumor suppressors, thus allowing AMPK activation while mitigating the growthlimiting effects of the enzyme (31,35). Under conditions of energetic stress and the demand of continuous cell proliferation, AMPK bestows tolerance of cancer cells to nutrient deprivation without restricting cell growth and proliferation (31).…”

“…In addition, the modulation of AMPK in normal and transformed cells often triggers the opposing effects due to differential deletion of downstream tumor suppressors, thus allowing AMPK activation while mitigating the growthlimiting effects of the enzyme (31,35). Under conditions of energetic stress and the demand of continuous cell proliferation, AMPK bestows tolerance of cancer cells to nutrient deprivation without restricting cell growth and proliferation (31). In fact, the decreased AMPK activity in prostate cancer cells challenged to certain energy-starved conditions enhances apoptotic cell death during androgen deprivation and hypoxia (30) and also diminishes their invasive capability when incubated in serum-free media containing adenosine (present study).…”

“…7D and E and Supplementary Table). Finally, we used a small-molecule AMPK inhibitor compound C capable of inhibiting phospho-AMPK activity in PC-3 and other cancer cells in a concentration-dependent fashion (30,31). Similarly to adenosine-pretreated cells, compound C significantly diminished the number of invaded MDA-MB-231 cells (Fig.…”