The nuclear protein Artemis promotes AMPK activation by stabilizing the LKB1-AMPK complex.

AMP-activated protein kinase (AMPK) is a hetero-trimeric Ser/Thr kinase composed of a catalytic α subunit and regulatory ß and γ subunits; it functions as an energy sensor that controls cellular energy homeostasis. In response to an increased cellular AMP/ATP ratio, AMPK is activated by phosphorylation at Thr172 in the α-subunit by upstream AMPK kinases (AMPKKs), including tumor suppressor liver kinase B1 (LKB1). To elucidate more precise molecular mechanisms of AMPK activation, we performed yeast two-hybrid screening and isolated the complementary DNA (cDNA) encoding the nuclear protein Artemis/DNA cross-link repair 1C (DCLRE1C) as an AMPKα2-binding protein. Artemis was found to co-immunoprecipitate with AMPKα2, and the co-localization of Artemis with AMPKα2 in the nucleus was confirmed by immunofluorescence staining in U2OS cells. Moreover, over-expression of Artemis enhanced the phosphorylation of AMPKα2 and the AMPK substrate acetyl-CoA carboxylase (ACC). Conversely, RNAi-mediated knockdown of Artemis reduced AMPK and ACC phosphorylation. In addition, Artemis markedly increased the physical association between AMPKα2 and LKB1. Taken together, these results suggest that Artemis functions as a positive regulator of AMPK signaling by stabilizing the LKB1-AMPK complex.

[A case of sigmoid colon cancer with temporary dysarthria associated with irinotecan].

A40 -year-old woman visited our hospital with adenocaricinoma of the sigmoid colon with multiple liver metastases and ovarian metastasis. Because of a stenosis of the primary tumor, she underwent a colostomy before chemotherapy. 5-fluorouracil and irinotecan and leucovorin(FOLFIRI)was selected as first-line chemotherapy. At the start of chemotherapy, just after the end of irinotecan and leucovorin administration, the patient developed dysarthria. There were no neurological abnormalities or hematological abnormalities. The treatment was temporarily discontinued, and the dysarthria completely disappeared within 90 minutes. 5-fluorouracil was administered after the disappearance of dysarthria. Within 60 minutes of the administration of irinotecan and leucovorin at the second chemotherapy treatment, the patient developed dysarthria again. The patient had no neurological or hematological abnormalities. Magnetic resonance imaging(MRI)showed no abnormalities. The treatment was stopped and dysarthria disappeared within 60 minutes as it did the first time. At each time, no treatment for dysarthria was performed. This patient refused to continue irinotecan because of dysarthria. Therefore, chemotherapy without irinotecan was continued for the third time onward. In the previous literature, 8 cases of dysarthria caused by irinotecan were reported as a rare toxicity. In all cases, dysarthria was temporary and reversible. Because the mechanism of dysarthria is unclear, specific treatment and precaution for dysarthria is not recommended. Since dysarthria is reversible, however, irinotecan might be continued until progression.

[A case of sigmoid colon cancer with lymphangitis carcinomatosa successfully treated with chemotherapies including molecular targeting drugs].

A 51-year-old man was referred to our hospital with adenocarcinoma of sigmoid colon with multiple lymph node metastasis. At the time of admission, he had dyspnea, and computed tomography (CT) showed typical signs of lymphangitis carcinomatosa of the lung. Combination of mFOLFOX6 and bevacizumab was started. After start of the therapy, CT revealed an improvement in lymphangitis carcinomatosa. 8 months later, the tumor assessment became progressive disease. FOLFIRI was started as the second-line chemotherapy, but the patient did not respond. Then, dyspnea emerged again, and CT indicated the lymphangitis carcinomatosa had become worse. So as the third-line chemotherapy, combination of irinotecan and cetuximab was started. Dyspnea immediately disappeared, and CT showed an improvement of lymphangitis carcinomatosa. In the previous literature, malignant tumor cases which accompany lymphangitis carcinomatosa might always have a poor course. Our case dramatically responded to the chemotherapy including molecular targeting drug and showed a long survival. So we conclude that aggressive chemotherapy including a molecular targeting drug may be recommended in a case of colorectal cancer which accompanies lymphangitis carcinomatosa of the lung.

[Second-line chemotherapy for colorectal cancer].

For the current metastatic colorectal cancer, FOLFIRI or FOLFOX is chosen as first-line chemotherapy. Second-line irinotecan-based chemotherapy is commonly used after first-line oxaliplatin-based chemotherapy. Of course, FOLFOX becomes the second-line if FOLFIRI becomes primary therapy. It is important that these regimens combine molecular targetting agents such as Bevacizumab or Cetuximab. The addition of these new agents offers a chance to further enhance the activity of conventional chemotherapy.