Small cell lung cancer (SCLC) is highly malignant lung tumor that spreads early throughout the body. It is characterized by neuroendocrine features such as neuropeptide production and N-CAM expression [1
]. At diagnosis in most cases, SCLC has already metastasized to regional lymph nodes and distant organs including brain, bone, liver, and adrenal gland, thus excluding the possibility of surgical resection. Currently, standard treatment against extended SCLC is chemotherapy including cisplatin and etoposide [2
]. Despite its high sensitivity to these anticancer drugs, SCLC rapidly develops recurrent tumors locally and at the distant organs. Such malignant phenotype is at least partially caused by acquired resistance to apoptotic cell death [3
]. Elucidation of its mechanisms is necessary to improve outcome of chemotherapy, but little has been clarified.
Tetraspanins are a family of membranous proteins that has characteristic structure spanning the membrane four times. Through association with other functional proteins including integrins, growth factor receptors, membrane proteases, and intracellular signaling molecules, tetraspanins organize multiprotein complexes at the tetraspanin-enriched microdomain (TEM) and regulate cell adhesion, migration, and survival [4
]. Among 33 members in humans, CD9 and CD82 are known as a metastasis suppressor of solid tumors. Clinical and pathological findings suggest that decreased expressions of these tetraspanins are associated with progression of cancers of breast, pancreas, colon, and esophagus, and nonsmall cell lung cancer (NSCLC) and thus with poor prognosis [6
We have shown that, among tetraspanins, CD9 is selectively absent in a majority of SCLC lines and SCLC tissues in contrast to NSCLC which frequently expresses CD9, and that ectopic expression of CD9 in SCLC cells suppresses integrin β1-dependent cell motility [8
] and promotes apoptotic cell death through attenuation of PI3K/Akt signaling [9
]. These results suggest that the absence of CD9 contributes to highly malignant phenotype of SCLC. We also found that CD9 expression is induced and cell motility is decreased when SCLC cells are exposed to cisplatin or etoposide [10
]. In the present study, we compared an SCLC cell line with its CD9 transfectant by a proteomics-based approach and found that a calcium-binding neuronal protein, calretinin, is upregulated in CD9-positive SCLC cells. We also show that calretinin mediates apoptotic cell death of SCLC.