CA9

Official Full Name

carbonic anhydrase 9

Organism

Homo sapiens

GeneID

768

Background

Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. They show extensive diversity in tissue distribution and in their subcellular localization. CA IX is a transmembrane protein and is one of only two tumor-associated carbonic anhydrase isoenzymes known. It is expressed in all clear-cell renal cell carcinoma, but is not detected in normal kidney or most other normal tissues. It may be involved in cell proliferation and transformation. This gene was mapped to 17q21.2 by fluorescence in situ hybridization, however, radiation hybrid mapping localized it to 9p13-p12. [provided by RefSeq, Jun 2014]

Synonyms

MN; CAIX;

Bio Chemical Class

Alpha-carbonic anhydrase

Protein Sequence

MAPLCPSPWLPLLIPAPAPGLTVQLLLSLLLLVPVHPQRLPRMQEDSPLGGGSSGEDDPLGEEDLPSEEDSPREEDPPGEEDLPGEEDLPGEEDLPEVKPKSEEEGSLKLEDLPTVEAPGDPQEPQNNAHRDKEGDDQSHWRYGGDPPWPRVSPACAGRFQSPVDIRPQLAAFCPALRPLELLGFQLPPLPELRLRNNGHSVQLTLPPGLEMALGPGREYRALQLHLHWGAAGRPGSEHTVEGHRFPAEIHVVHLSTAFARVDEALGRPGGLAVLAAFLEEGPEENSAYEQLLSRLEEIAEEGSETQVPGLDISALLPSDFSRYFQYEGSLTTPPCAQGVIWTVFNQTVMLSAKQLHTLSDTLWGPGDSRLQLNFRATQPLNGRVIEASFPAGVDSSPRAAEPVQLNSCLAAGDILALVFGLLFAVTSVAFLVQMRRQHRRGTKGGVSYRPAEVAETGA

Open

Disease

Breast cancer, Lymphoma, Renal cell carcinoma, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

9 +

Discontinued Drug

2 +

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Detailed Information

Carbonic anhydrase IX (CA9), also known as G250 or MN, has emerged as a fascinating target in cancer research due to its unique characteristics and crucial role in tumor progression. Mostly produced in cancer cells and almost nonexistent in normal tissues, this transmembrane protein has attracted the interest of researchers all over for its possibilities in cancer detection and therapy.

Structure and Function

A multidomain protein with unique structural features, CA9 is functional thanks in part to Comprising an intracellular tail (IC), a transmembrane domain (TM), and an extracellular section including a catalytic domain (CA), and a proteoglycan-like domain (PG), the protein is the special PG domain of CA9 distinguishes it from other carbonic anhydrites and is very important for cell adhesion and cancer metastases.

At the bottom of a cone-shaped cavity spanning the protein surface to its center, CA9's catalytic domain comprises a zinc ion (Zn²⁺). Hydrophobic and hydrophilic sections of this cavity provide an ideal habitat for their enzymatic action. Asp132, Thr69, and Arg130 are among many unusual amino acid residues that help CA9 to be specific and provide chances for selective inhibitor design.

CA9 in Tumor Microenvironment

In terms of cancer biology, CA9's main role is pH control inside the tumor microenvironment. Rapid proliferating cancer cells produce hypoxic areas within the tumor bulk. Cells change to glycolytic metabolism under these circumstances, generating more acidic byproducts. By catalyzing the reversible hydration of carbon dioxide to bicarbonate and protons, CA9 helps maintain an alkaline intracellular pH while producing an acidic extracellular environment, therefore enabling adaptation to this demanding environment.

The course of a tumor depends much on this pH control. Whereas cancer cell survival, invasion, and metastases are favored by the acidic extracellular pH, normal cells find their environment unfriendly. Moreover, activation of CA9 has been connected to many facets of cancer biology, including:

1. Tumor Growth and Metabolism: CA9 helps cancer cells to adapt to hypoxic environments, therefore allowing their continuous multiplication independent of oxygen availability. Recent research has shown its importance in nutritional delivery, notably in amino acid movement. Different amino acid transporters may be modulated by CA9, therefore influencing glutamine intake and metabolism—two vital processes for cancer cell survival and proliferation.

2. Cancer Cell Invasion and Metastasis: Outside of pH control, CA9 affects cancer cell adhesion, migration, and invasion. The protein influences cell-cell adhesion by interacting with β-catenin and E-cadherin, therefore encouraging cell migration. Through interactions with matrix metalloproteinases—especially MMP-14—CA9 has also been linked to extracellular matrix remodeling and focal adhesion turnover.

3. Cancer Stemness and Therapy Resistance: Maintaining cancer stem cell characteristics and hence supporting therapy resistance has become mostly dependent on CA9. CA9 controls stemness in breast cancer using the mTORC1 axis, therefore boosting the transcription of important stemness drivers like Notch1 and Jagged1. Through interactions with survival pathways and lowered DNA damage in acidic conditions, CA9 also helps with both radioresistance and chemoresistance.

Figure 1 illustrates the biological features triggered in cancer cells and their microenvironment by the upregulation of the CA9 gene due to hypoxia or oncogenic pathways. Figure 1. Schematic showing the biological features activated in cancer cells and their microenvironment by CA9 gene upregulation due to hypoxia or oncogenic pathways. (Benej M, et al., 2014)

Clinical Implications and Therapeutic Potential

CA9 is a desirable target for cancer treatment and detection because of its unusual expression pattern: highly expressed in many tumors yet almost nonexistent in normal tissues. While lacking in benign lesions, CA9 expression has been seen in 86% of clear cell instances in renal cell carcinoma. Bladder cancer, non-small cell lung cancer, and cervical cancer have also shown similar trends wherein CA9 expression typically corresponds with poor prognosis and enhanced metastatic potential. Therapeutic strategies targeting CA9 are being actively developed, with several approaches showing promise:

1. Small Molecule Inhibitors: These compounds target the catalytic domain of CA9, interfering with its pH-regulating function.
2. Monoclonal Antibodies: These can be used both for targeting CA9-expressing tumors and for diagnostic imaging.
3. Combination Therapies: CA9 inhibition has shown potential in enhancing the efficacy of conventional chemotherapy and radiotherapy.

Recent advances have also underlined the possibility of focusing on CA9 in the framework of alkaline cell death, a special kind of cell death that takes advantage of the pH dysregulation sensitivity of cancer cells. In preclinical studies, compounds such as JTC801 have shown promise by causing alkaline cell death in many cancer forms and displaying little toxicity to normal tissues.

References:

Benej M, Pastorekova S, Pastorek J. Carbonic anhydrase IX: regulation and role in cancer. Subcell Biochem. 2014;75:199-219.
Fecikova S, Csaderova L, Belvoncikova P, et al. Can hypoxia marker carbonic anhydrase IX serve as a potential new diagnostic marker and therapeutic target of non-small cell lung cancer?. Neoplasma. 2024;71(2):123-142.
Rowe SP, Islam MZ, Viglianti B, et al. Molecular imaging for non-invasive risk stratification of renal masses. Diagn Interv Imaging. 2024;105(9):305-310.

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