Neuregulin Promotes Incomplete Autophagy of Prostate Cancer Cells That Is Independent of mTOR Pathway Inhibition

Abstract

BackgroundGrowth factors activating the ErbB receptors have been described in prostate tumors. The androgen dependent prostate cancer cell line, LNCaP, expresses the ErbB-1, ErbB-2 and ErbB-3 receptor tyrosine kinases. Previously, it was demonstrated that NRG activates ErbB-2/ErbB-3 heterodimers to induce LNCaP cell death, whereas, EGF activates ErbB-1/ErbB-1 or ErbB-1/ErbB-2 dimers to induce cell growth and survival. It was also demonstrated that PI3K inhibitors repressed this cell death suggesting that in androgen deprived LNCaP cells, NRG activates a PI3K-dependent pathway associated with cell death.Methodology/Principal FindingsIn the present study we demonstrate that NRG induces autophagy in LNCaP cells, using LC3 as a marker. However, the autophagy induced by NRG may be incomplete since p62 levels elevate. We also demonstrated that NRG- induced autophagy is independent of mammalian target of rapamycin (mTOR) inhibition since NRG induces Akt and S6K activation. Interestingly, inhibition of reactive oxygen species (ROS) by N-acetylcysteine (NAC), inhibited NRG-induced autophagy and cell death. Our study also identified JNK and Beclin 1 as important components in NRG-induced autophagy and cell death. NRG induced elevation in JNK phosphorylation that was inhibited by NAC. Moreover, inhibitor of JNK inhibited NRG-induced autophagy and cell death. Also, in cells overexpressing Bcl-2 or cells expressing sh-RNA against Beclin 1, the effects of NRG, namely induction of autophagy and cell death, were inhibited.Conclusions/SignificanceThus, in LNCaP cells, NRG-induces incomplete autophagy and cell death that depend on ROS levels. These effects of NRG are mediated by signaling pathway that activates JNK and Beclin 1, but is independent of mTOR inhibition.

microRNA-32 induces radioresistance by targeting DAB2IP and regulating autophagy in prostate cancer cells

“…Autophagy is an intracellular self-protective mechanism that functions by preventing the toxic accumulation of damaged components and by recycling these components to sustain metabolic homoeostasis ( 33 , 34 ). Upregulated autophagy has been identified in a wide variety of cancer cells that undergo metabolic and therapeutic stress, and the process contributes to the resistance to chemotherapy by a range of tumor types ( 35 , 36 ). The blocking of autophagy in cancer cells is emerging as a novel approach to enhance the sensitivity of therapy in cancers ( 37 ).…”

Pazopanib and sunitinib trigger autophagic and non-autophagic death of bladder tumour cells

“…Incomplete autophagy has been found to trigger cell death (Schmukler et al , 2012), and lysosomes are important players in triggering mitochondrial-dependent apoptosis, mitochondrial-independent necrosis and autophagy (Kroemer and Jäättelä, 2005; Kirkegaard and Jäättelä, 2009; Groth-Pedersen and Jäättelä, 2010). …”

Cellular metabolic and autophagic pathways: Traffic control by redox signaling

“…Interestingly, many of the proteins in the autophagy and cell death pathways contain cysteine residues essential for normal function, and can be modified by aldehydes or other reactive electrophiles, inhibiting their function. N-acetyl cysteine has been shown to reverse the activation of autophagy by neuregulin in prostate cancer cells, and also prevents the hypoxia induced autophagic cell death of retinal ganglion cells [202, 203]. In a methamphetamine-induced model of Parkinson’s disease in N27 cells, N-acetyl cysteine can prevent dopaminergic cell death by preventing the depletion of GSH and activating autophagy [204].…”