Beclin 1 Promotes Endosome Recruitment of Hepatocyte Growth Factor Tyrosine Kinase Substrate to Suppress Tumor Proliferation

Abstract

◥Beclin 1 has nonautophagic functions that include its ability to regulate endocytic receptor trafficking. However, the contribution of this function to tumor suppression is poorly understood. Here, we provide in vivo evidence that Beclin 1 suppresses tumor proliferation by regulating the endocytic trafficking and degradation of the EGFR and transferrin (TFR1) receptors. Beclin 1 promoted endosomal recruitment of hepatocyte growth factor tyrosine kinase substrate (HRS), which was necessary for sorting surface receptors to intraluminal vesicles for signal silencing and lysosomal degra-dation. In tumors with low Beclin 1 expression, endosomal HRS recruitment was diminished and receptor function was sustained. Collectively, our results demonstrate a novel role for Beclin 1 in impeding tumor growth by coordinating the regulation of key growth factor and nutrient receptors. These data provide an explanation for how low levels of Beclin 1 facilitate tumor proliferation and contribute to poor cancer outcomes.Significance: Beclin 1 controls the trafficking fate of growth regulatory receptors to suppress tumor proliferation.

Newcastle-disease-virus-induced ferroptosis through nutrient deprivation and ferritinophagy in tumor cells

“…Consistent with this, our results show that ALOX12 is upregulated by NDV infection and ACSL4 activation is not necessary for NDV-induced ferroptosis (Figure S2G). Recent findings report AMPK-mediated beclin-1 phosphorylation induces ferroptosis (Matthew-Onabanjo et al, 2020;Song et al, 2018). However, Lee et al showed that PUFAs can be synthesized from the basic building block acetyl coenzyme A carboxylase and that AMPK suppresses ferroptosis by inhibiting ACC (Lee et al, 2020).…”

Autophagy Regulation on Cancer Stem Cell Maintenance, Metastasis, and Therapy Resistance

“…Moreover, beclin1 has been demonstrated to have non-autophagy functions such as regulation of endocytic receptor trafficking, apoptosis, and inflammation [ 90 ]. One study illustrated that beclin1 is able to regulate growth factor and nutrient receptors, thus inhibiting tumor proliferation [ 91 ]. Therefore, it is crucial to clarify the role that autophagy plays in CSCs and cancer development.…”

Newcastle disease virus induced ferroptosis through p53-SLC7A11-GPX4 axis mediated nutrient deprivation in tumor cells

“…Consistent with this, our results show that ALOX12 is upregulated by NDV infection and ACSL4 activation is not necessary for NDVinduced ferroptosis (data not shown). Recent findings report Ampk-mediated beclin-1 phosphorylation induces ferroptosis (Matthew-Onabanjo et al, 2020;Song et al, 2018). However, Lee et al showed that PUFAs can be synthesized from the basic building block acetyl coenzyme A carboxylase and that AMPK suppresses ferroptosis by inhibiting ACC.…”