LncRNA CamK-A Regulates Ca2+-Signaling-Mediated Tumor Microenvironment Remodeling

Abstract

Cancer cells entail metabolic adaptation and microenvironmental remodeling to survive and progress. Both calcium (Ca) flux and Ca-dependent signaling play a crucial role in this process, although the underlying mechanism has yet to be elucidated. Through RNA screening, we identified one long noncoding RNA (lncRNA) named CamK-A (lncRNA for calcium-dependent kinase activation) in tumorigenesis. CamK-A is highly expressed in multiple human cancers and involved in cancer microenvironment remodeling via activation of Ca-triggered signaling. Mechanistically, CamK-A activates Ca/calmodulin-dependent kinase PNCK, which in turn phosphorylates IκBα and triggers calcium-dependent nuclear factor κB (NF-κB) activation. This regulation results in the tumor microenvironment remodeling, including macrophage recruitment, angiogenesis, and tumor progression. Notably, our human-patient-derived xenograft (PDX) model studies demonstrate that targeting CamK-A robustly impaired cancer development. Clinically, CamK-A expression coordinates with the activation of CaMK-NF-κB axis, and its high expression indicates poor patient survival rate, suggesting its role as a potential biomarker and therapeutic target.

The Clinical Kinase Index: Prioritizing Understudied Kinases as Targets for the Treatment of Cancer

“…The understudied multi-functional CAMK kinases ( CAMK1D, CAMK1G, CAMKK1, PNCK ) are overexpressed in 12 cancers, with PNCK being overexpressed in 9 alone. PNCK (Tbio) mRNA expression and activity has recently been linked to renal cell carcinoma progression and survival [10], breast cancer tumor microenvironment remodeling [31] and decreased sensitivity to chemotherapies such as temozolomide [32]. PNCK is highly overexpressed in KIRC (>5 log 2 FC), LUSC (>6 log 2 FC), and LIHC (>6 log 2 FC).…”

Small Protein Hidden in lncRNA LOC90024 Promotes “Cancerous” RNA Splicing and Tumorigenesis

“…Accumulating evidence has shown that dysregulated lncRNAs, as RNA molecules, contribute to various cancer hallmarks. [ 11 ] We found that lncRNA LOC90024 actually encodes a 130‐aa small protein, which we named SRSP. LOC90024 ‐encoded small protein SRSP, but not LOC90024 lncRNA itself, exerts oncogenic functions.…”

“…Consequently, dysregulation of lncRNAs in cancers contributes to the hallmarks of cancers and the survival time of cancer patients; thus, they are attractive potential biomarkers and therapeutic targets. [ 8,10,11 ] However, the functional roles of lncRNA in “cancerous” RNA splicing remain to be explored.…”

Immunometabolism features of metabolic deregulation and cancer

“…The ability of tumour cells to regulate the local nutrients 91 and waste products of tumour metabolism also play a critical role in determining the fate of metabolic deregulation of cancer. 92 Moreover, recent emergence of LncRNAs and their metabolic implication in cancers [93][94][95] provides an interesting dimension to this multi-headed disease.…”