The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer

Jin, Lingtao; Chun, Jaemoo; Pan, Chaoyun; Kumar, Avi; Zhang, Guojing; Ha, Youna; Li, Dan; Alesi, Gina N.; Kang, Yibin; Zhou, Lu; Yu, Wen Mei; Magliocca, Kelly R.; Khuri, Fadlo R.; Qu, Cheng‐Kui; Metallo, Christian M.; Owonikoko, Taofeek K.; Kang, Sumin

doi:10.1016/j.molcel.2017.11.025

Cited by 251 publications

(189 citation statements)

References 46 publications

Supporting

Mentioning

166

Contrasting

Order By: Relevance

“…CaMKK2 and its downstream kinases, CaMKI, CaMKIV, and AMPK have well-established roles in energy homeostasis, nutrient responses, and cell growth (Marcelo et al, 2016). Furthermore, CaMKK2 is upregulated in multiple tumor types, and its inhibition reduces cell proliferation and tumorigenicity in vivo (Lin et al, 2015;Jin et al, 2018). Our work reveals that, in addition to receptors for circulating factors, such as hormones and metabolites (Swulius and Waxham, 2008;Marcelo et al, 2016), also mechanical stimuli can activate CaMKK2 in cells.…”

Section: Discussionmentioning

confidence: 74%

CaMKK2 Regulates Mechanosensitive Assembly of Contractile Actin Stress Fibers

2018

View full text Add to dashboard Cite

Stress fibers are contractile actomyosin bundles that guide cell adhesion, migration, and morphogenesis. Their assembly and alignment are under precise mechanosensitive control. Thus, stress fiber networks undergo rapid modification in response to changes in biophysical properties of the cell's surroundings. Stress fiber maturation requires mechanosensitive activation of 5'AMP-activated protein kinase (AMPK), which phosphorylates vasodilator-stimulated phosphoprotein (VASP) to inhibit actin polymerization at focal adhesions. Here, we identify Ca-calmodulin-dependent kinase kinase 2 (CaMKK2) as a critical upstream factor controlling mechanosensitive AMPK activation. CaMKK2 and Ca influxes were enriched around focal adhesions at the ends of contractile stress fibers. Inhibition of either CaMKK2 or mechanosensitive Ca channels led to defects in phosphorylation of AMPK and VASP, resulting in a loss of contractile bundles and a decrease in cell-exerted forces. These data provide evidence that Ca, CaMKK2, AMPK, and VASP form a mechanosensitive signaling cascade at focal adhesions that is critical for stress fiber assembly.

show abstract

Section: Discussionmentioning

confidence: 74%

CaMKK2 Regulates Mechanosensitive Assembly of Contractile Actin Stress Fibers

2018

View full text Add to dashboard Cite

show abstract

“…We found that cholangiocarcinoma cells with differential RMP expression did not show differences in proliferation or migration under 2D culture conditions in vitro , although RMP overexpression promoted an increase in the colony formation capacity in a soft agar 3D environment of stimulation. After epithelial cells detach from the basement membrane, anoikis tends to occur, and some cells can continue to resist this apoptosis, showing anchorage‐independent growth . It has been reported that cells must surmount different kinds of stress, including increased ROS levels, to maintain anchorage‐independent growth .…”

Section: Discussionmentioning

confidence: 99%

RPB5‐Mediating Protein Promotes Cholangiocarcinoma Tumorigenesis and Drug Resistance by Competing With NRF2 for KEAP1 Binding

et al. 2020

View full text Add to dashboard Cite

BaCKgRoUND aND aIMS:Cancer cell survival depends on the balance between reactive oxygen species production and scavenging, which is regulated primarily by NRF2 during tumorigenesis. Here, we demonstrate that deletion of RBP5mediating protein (RMP) in an autonomous mouse model of intrahepatic cholangiocarcinoma (ICC) delays tumor progression. appRoaCH aND ReSUltS: RMP-overexpressing tumor cells exhibited enhanced tolerance to oxidative stress and apoptosis. Mechanistically, RMP competes with NRF2 for binding to the Kelch domain of KEAP1 (Kelch-like ECH-associated protein 1) through the E**E motif, leading to decreased NRF2 degradation via ubiquitination, thus increasing NRF2 nuclear translocation and downstream transactivation of antioxidant genes. This RMP-KEAP1-NRF2 axis promotes ICC tumorigenesis, metastasis, and drug resistance. Consistent with these findings, the RMP level in human ICC is positively correlated with the protein level of NRF2 and is associated with poor prognosis.CoNClUSIoN: These findings reveal that RMP is involved in the oxidative stress defense program and could be exploited for targeted cancer therapies. (Hepatology 2020;71:2005-2022.

show abstract

“…Unfortunately, these authors used 5-fold greater concentrations of palbociclib to our own which is above the safe plasma C max concentration, and our ability of palbociclib to enhance AMPKα T172 phosphorylation occurs in cells with very low/no LKB-1 expression such as HT1080 (sarcoma), A549 and H460 (NSCLC) and HCT116 (colon). 21 However, others have reported that palbociclib in a CDK4/6-independent fashion activates the AMPK. 22 And, that this effect may be due to inhibition of other targets such as CDK9, which has a similar consensus sequence to that of CDK4/6 and ERK1/2.…”

Section: Discussionmentioning

confidence: 99%

Palbociclib augments Neratinib killing of tumor cells that is further enhanced by HDAC inhibition

Booth

Roberts

Rais

et al. 2018

Cancer Biology & Therapy

View full text Add to dashboard Cite

Cancers expressing mutant RAS are associated with a weaker response to chemotherapy and a shorter overall patient survival. We have demonstrated that the irreversible inhibitor of ERBB1/2/4, neratinib, inhibits ERBB1/2/4 and causes their internalization and autolysosomal degradation. Fellow-traveler membrane proteins with RTKs, including mutant K-/N-RAS, were also degraded. We discovered that the CDK4/6 inhibitor palbociclib increased autophagosome and then autolysosome levels in a time dependent fashion, did not reduce mTOR activity, and interacted with temsirolimus to kill. Neratinib and palbociclib interacted in a greater than additive manner to increase autophagosome and then autolysosome levels in a time dependent fashion, and to cause tumor cell killing. Killing required the expression of ATM and AMPKα, Beclin1 and ATG5, BAX and BAK and of AIF, but not of caspase 9. In some cells over-expression of BCL-XL was protective whereas in others it was ineffective. The lethality of [neratinib + palbociclib] was modestly enhanced by the PDE5 inhibitor sildenafil and strongly enhanced by the HDAC inhibitor sodium valproate. This was associated with K-RAS degradation and a greater than additive increase in autophagosome and autolysosome levels. Killing by the three-drug combination required ATM and AMPKα, and, to a greater extent, Beclin1 and ATG5. In vivo, [valproate + palbociclib] and [neratinib + valproate + palbociclib] interacted to suppress the growth of a carboplatin/paclitaxel resistant PDX ovarian tumors that express a mutant N-RAS. Our data support performing a future three-drug trial with these agents.

show abstract

The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer

Cited by 251 publications

References 46 publications

CaMKK2 Regulates Mechanosensitive Assembly of Contractile Actin Stress Fibers

CaMKK2 Regulates Mechanosensitive Assembly of Contractile Actin Stress Fibers

RPB5‐Mediating Protein Promotes Cholangiocarcinoma Tumorigenesis and Drug Resistance by Competing With NRF2 for KEAP1 Binding

Palbociclib augments Neratinib killing of tumor cells that is further enhanced by HDAC inhibition

Contact Info

Product

Resources

About