A malaria drug triggers tumor cell apoptosis
Chloroquine is a drug that has long been used to treat and prevent malaria. This antimalarial agent sometimes is given off-label to treat other diseases such as arthritis, lupus, and rheumatoid arthritis. In addition, accumulating evidence suggests that chloroquine is capable of inhibiting tumor growth and metastases.
Now, a new study reports that chloroquine induces the secretion of a tumor suppressor protein from normal cells in mice and cancer patients, which triggers paracrine apoptosis of cancer cells and inhibits metastatic tumor growth.
The tumor suppressor protein, called Prostate apoptosis response-4 (Par-4), has pro-apoptotic effects, and is known to induce apoptosis selectively in cancer cells. The new study revealed that chloroquine induces Par-4 secretion via the classical secretory pathway that involves the activation of p53. p53 induces an enzyme called Rab8b that facilitates Par-4 transport. "Chloroquine-induced Par-4 secretion depends on p53," the researchers noted.
Secreted Par-4 induces apoptosis by binding to the cell-surface protein GRP78. Normal cells tend to express no or low level of GRP78, so normal cells are usually resistant to Par-4-induced apoptosis. By contrast, cancer cells that express high level of GRP78 are susceptible to Par-4-induced apoptosis.
p53 is also a tumor suppressor protein, and it is frequently mutated in cancer which makes the disease hard to treat. The new study revealed that chloroquine could cause normal cells that have wide-type p53 to secrete Par-4, which in turn triggers apoptosis and inhibits metastasis in cancer cells that have defective p53. This represents a way to combat cancer with p53 variations.
The study, led by Vivek Rangnekar from University of Kentucky and published in Cell Reports, provides insights into the mechanism of how the drug chloroquine induces tumor cell apoptosis and suppresses metastasis.
CusAb is a manufacturer of proteins and antibodies. The following are Par-4 and GRP78 related products.
Par-4 Recombinant Protein
, Par-4 Antibody
, GRP78 Recombinant Protein
, GRP78 Antibody
, Rab8b Recombinant Protein
, Rab8b Antibody