PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth

Mami Morita¹, Taku Sato², Miyuki Nomura³, Yoshimi Sakamoto³, Yui Inoue³, Ryota Tanaka², Shigemi Ito³, Koreyuki Kurosawa³, Kazunori Yamaguchi⁴, Yuki Sugiura⁵, Hiroshi Takizaki⁶, Yoji Yamashita³, Ryuichi Katakura³, Ikuro Sato⁷, Masaaki Kawai³, Yoshinori Okada⁸, Hitomi Watanabe⁹, Gen Kondoh⁹, Shoko Matsumoto¹⁰, Ayako Kishimoto¹⁰, Miki Obata¹¹, Masaki Matsumoto¹², Tatsuro Fukuhara¹³, Hozumi Motohashi¹⁴, Makoto Suematsu⁵, Masaaki Komatsu¹¹, Keiichi I Nakayama¹², Toshio Watanabe¹⁰, Tomoyoshi Soga¹⁵, Hiroshi Shima¹⁶, Makoto Maemondo¹⁷, Nobuhiro Tanuma¹⁸

Affiliations

¹ Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan; Division of Respiratory Oncology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Department of Respiratory Medicine, Miyagi Cancer Center Hospital, Natori 981-1293, Japan.
² Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan; Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
³ Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan.
⁴ Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan.
⁵ Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
⁶ Division of Cancer Molecular Biology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
⁷ Tissue Bank, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan.
⁸ Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
⁹ Laboratory of Animal Experiments for Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
¹⁰ Department of Biological Science, Graduate School of Humanities and Sciences, Nara Women's University, Nara 630-8506, Japan.
¹¹ Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
¹² Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyusyu University, Fukuoka 812-8582, Japan.
¹³ Department of Respiratory Medicine, Miyagi Cancer Center Hospital, Natori 981-1293, Japan.
¹⁴ Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
¹⁵ Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan.
¹⁶ Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan; Division of Cancer Molecular Biology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
¹⁷ Division of Respiratory Oncology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Department of Respiratory Medicine, Miyagi Cancer Center Hospital, Natori 981-1293, Japan.
¹⁸ Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan; Division of Cancer Molecular Biology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan. Electronic address: ntanuma@med.tohoku.ac.jp.

PMID: 29533781
DOI: 10.1016/j.ccell.2018.02.004

Free article

PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth

Mami Morita et al. Cancer Cell. 2018.

Free article

. 2018 Mar 12;33(3):355-367.e7.

doi: 10.1016/j.ccell.2018.02.004.

Authors

Affiliations

¹ Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan; Division of Respiratory Oncology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Department of Respiratory Medicine, Miyagi Cancer Center Hospital, Natori 981-1293, Japan.
² Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan; Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
³ Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan.
⁴ Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan.
⁵ Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
⁶ Division of Cancer Molecular Biology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
⁷ Tissue Bank, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan.
⁸ Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
⁹ Laboratory of Animal Experiments for Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
¹⁰ Department of Biological Science, Graduate School of Humanities and Sciences, Nara Women's University, Nara 630-8506, Japan.
¹¹ Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
¹² Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyusyu University, Fukuoka 812-8582, Japan.
¹³ Department of Respiratory Medicine, Miyagi Cancer Center Hospital, Natori 981-1293, Japan.
¹⁴ Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
¹⁵ Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan.
¹⁶ Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan; Division of Cancer Molecular Biology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
¹⁷ Division of Respiratory Oncology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Department of Respiratory Medicine, Miyagi Cancer Center Hospital, Natori 981-1293, Japan.
¹⁸ Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan; Division of Cancer Molecular Biology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan. Electronic address: ntanuma@med.tohoku.ac.jp.

PMID: 29533781
DOI: 10.1016/j.ccell.2018.02.004

Abstract

Expression of PKM2, which diverts glucose-derived carbon from catabolic to biosynthetic pathways, is a hallmark of cancer. However, PKM2 function in tumorigenesis remains controversial. Here, we show that, when expressed rather than PKM2, the PKM isoform PKM1 exhibits a tumor-promoting function in KRAS^G12D-induced or carcinogen-initiated mouse models or in some human cancers. Analysis of Pkm mutant mouse lines expressing specific PKM isoforms established that PKM1 boosts tumor growth cell intrinsically. PKM1 activated glucose catabolism and stimulated autophagy/mitophagy, favoring malignancy. Importantly, we observed that pulmonary neuroendocrine tumors (NETs), including small-cell lung cancer (SCLC), express PKM1, and that PKM1 expression is required for SCLC cell proliferation. Our findings provide a rationale for targeting PKM1 therapeutically in certain cancer subtypes, including pulmonary NETs.

Keywords: PKM; PKM1; PKM2; autophagy; glucose metabolism; lung neuroendocrine tumor; mitophagy; small-cell lung cancer.

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Comment in

Glucose Metabolism in Cancer: The Saga of Pyruvate Kinase Continues.
Allen AE, Locasale JW. Allen AE, et al. Cancer Cell. 2018 Mar 12;33(3):337-339. doi: 10.1016/j.ccell.2018.02.008. Cancer Cell. 2018. PMID: 29533776 Free PMC article.

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PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth

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PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth

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