ATF4/CEMIP/PKCα promotes anoikis resistance by enhancing protective autophagy in prostate cancer cells

Abstract

The survival of cancer cells after detaching from the extracellular matrix (ECM) is essential for the metastatic cascade. The programmed cell death after detachment is known as anoikis, acting as a metastasis barrier. However, the most aggressive cancer cells escape anoikis and other cell death patterns to initiate the metastatic cascade. This study revealed the role of cell migration-inducing protein (CEMIP) in autophagy modulation and anoikis resistance during ECM detachment. CEMIP amplification during ECM detachment resulted in protective autophagy induction via a mechanism dependent on the dissociation of the B-cell lymphoma-2 (Bcl-2)/Beclin1 complex. Additional investigation revealed that acting transcription factor 4 (ATF4) triggered CEMIP transcription and enhanced protein kinase C alpha (PKCα) membrane translocation, which regulated the serine70 phosphorylation of Bcl-2, while the subsequent dissociation of the Bcl-2/Beclin1 complex led to autophagy. Therefore, CEMIP antagonization attenuated metastasis formation in vivo. In conclusion, inhibiting CEMIP-mediated protective autophagy may provide a therapeutic strategy for metastatic prostate cancer (PCa). This study delineates a novel role of CEMIP in anoikis resistance and provides new insight into seeking therapeutic strategies for metastatic PCa.

CircCEMIP promotes anoikis-resistance by enhancing protective autophagy in prostate cancer cells

“…However, significantly higher circURI1 expression is evident in gastric cancer than in the corresponding adjacent nontumor specimens, inhibiting cell migration and invasion in vitro and gastric cancer metastasis in vivo [ 35 ]. Previous studies by our team have shown that CEMIP is upregulated in PCa and promotes PCa cell anoikis-resistance via autophagic activation [ 13 ]. This study further explored the role of CEMIP and circCEMIP (hsa_circ_0004585) cyclization products in PCa progression, revealing that circCEMIP was significantly upregulated in the PCa tissues and cell lines.…”

“…Moreover, TM9SF4 overexpression promoted PCa cell anoikis-resistance by inhibiting mTOR activity to facilitate autophagy, while the miR-1248 transcriptional regulation of TM9SF4 significantly promoted this effect. The inactivation of the mTOR pathway was essential for autophagic activation, providing energy support for PCa cell anoikis resistance and metastasis [ 13 ]. Furthermore, circ_0004585 encouraged PCa progression via miR-1248 sponging, promoting TM9SF4 expression.…”

“…Recent studies by our team have shown that CEMIP is upregulated in PCa and promotes its progression by regulating metabolic reprogramming [ 12 ]. Furthermore, CEMIP promotes PCa cells anoikis resistance and metastasis by activating protective autophagy [ 13 ]. However, the regulatory and functional mechanisms of circCMEIP in tumorigenesis and aggression remain elusive.…”

Anoikis resistance in diffuse glioma: The potential therapeutic targets in the future

“…One review concluded that protective autophagy is induced via integrin-focal adhesion signaling ( 143 ). Another in vivo study specified the ATF4/CEMIP/PKCα pathway as a trigger of protective autophagy ( 144 ). A study in glioma, however, revealed the MDA-9/Syntenin pathway as the key regulator in maintaining protective autophagy ( 145 ).…”

KIAA1199 Correlates With Tumor Microenvironment and Immune Infiltration in Lung Adenocarcinoma as a Potential Prognostic Biomarker

“…KIAA1199, also known as cell migration inducing protein (CEMIP) or hyaluronan binding protein (HYBID), was reported to cause non-syndromic hearing loss and depolymerize hyaluronic acid (HA) [12,13]. In recent years, welldocumented studies have demonstrated that KIAA1199 plays a role in promoting malignant progression and predicts poor prognosis of cancer patients, including gastric cancer [14][15][16], pancreatic cancer [17], colorectal cancer [18,19], prostate cancer [20,21] and so on. Studies have shown that KIAA1199 can promote sorafenib tolerance and the metastasis of hepatocellular carcinoma [22], facilitate extracellular matrix-detached prostate cancer cell survival by inhibiting ferroptosis [23] and accelerate metastasis in other tumors [18][19][20].…”