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

Mami Morita, Taku Sato, Miyuki Nomura, Yoshimi Sakamoto, Yui Inoue, Ryota Tanaka, Shigemi Ito, Koreyuki Kurosawa, Kazunori Yamaguchi, Yuki Sugiura, Hiroshi Takizaki, Yoji Yamashita, Ryuichi Katakura, Ikuro Sato, Masaaki Kawai, Yoshinori Okada, Hitomi Watanabe, Gen Kondoh, Shoko Matsumoto, Ayako KishimotoMiki Obata, Masaki Matsumoto, Tatsuro Fukuhara, Hozumi Motohashi, Makoto Suematsu, Masaaki Komatsu, Keiichi I. Nakayama, Toshio Watanabe, Tomoyoshi Soga, Hiroshi Shima, Makoto Maemondo, Nobuhiro Tanuma

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 KRASG12D-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. The relative importance of PKM isoforms in tumor growth has been controversial. Morita et al. show that PKM1 promotes the growth of multiple tumor models using mouse lines expressing PKM1 or PKM2 from the endogenous Pkm locus. PKM1 is expressed in human SCLC, and it is important for SCLC cell proliferation.

Original languageEnglish
Pages (from-to)355-367.e7
JournalCancer Cell
Volume33
Issue number3
DOIs
Publication statusPublished - 2018 Mar 12

Fingerprint

Small Cell Lung Carcinoma
Growth
Neoplasms
Protein Isoforms
Neuroendocrine Tumors
Mitochondrial Degradation
Cell Proliferation
Glucose
Lung
Biosynthetic Pathways
Autophagy
Carcinogens
Carcinogenesis
Carbon

Keywords

  • autophagy
  • glucose metabolism
  • lung neuroendocrine tumor
  • mitophagy
  • PKM
  • PKM1
  • PKM2
  • small-cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Morita, M., Sato, T., Nomura, M., Sakamoto, Y., Inoue, Y., Tanaka, R., ... Tanuma, N. (2018). PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth. Cancer Cell, 33(3), 355-367.e7. https://doi.org/10.1016/j.ccell.2018.02.004

PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth. / Morita, Mami; Sato, Taku; Nomura, Miyuki; Sakamoto, Yoshimi; Inoue, Yui; Tanaka, Ryota; Ito, Shigemi; Kurosawa, Koreyuki; Yamaguchi, Kazunori; Sugiura, Yuki; Takizaki, Hiroshi; Yamashita, Yoji; Katakura, Ryuichi; Sato, Ikuro; Kawai, Masaaki; Okada, Yoshinori; Watanabe, Hitomi; Kondoh, Gen; Matsumoto, Shoko; Kishimoto, Ayako; Obata, Miki; Matsumoto, Masaki; Fukuhara, Tatsuro; Motohashi, Hozumi; Suematsu, Makoto; Komatsu, Masaaki; Nakayama, Keiichi I.; Watanabe, Toshio; Soga, Tomoyoshi; Shima, Hiroshi; Maemondo, Makoto; Tanuma, Nobuhiro.

In: Cancer Cell, Vol. 33, No. 3, 12.03.2018, p. 355-367.e7.

Research output: Contribution to journalArticle

Morita, M, Sato, T, Nomura, M, Sakamoto, Y, Inoue, Y, Tanaka, R, Ito, S, Kurosawa, K, Yamaguchi, K, Sugiura, Y, Takizaki, H, Yamashita, Y, Katakura, R, Sato, I, Kawai, M, Okada, Y, Watanabe, H, Kondoh, G, Matsumoto, S, Kishimoto, A, Obata, M, Matsumoto, M, Fukuhara, T, Motohashi, H, Suematsu, M, Komatsu, M, Nakayama, KI, Watanabe, T, Soga, T, Shima, H, Maemondo, M & Tanuma, N 2018, 'PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth', Cancer Cell, vol. 33, no. 3, pp. 355-367.e7. https://doi.org/10.1016/j.ccell.2018.02.004
Morita M, Sato T, Nomura M, Sakamoto Y, Inoue Y, Tanaka R et al. PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth. Cancer Cell. 2018 Mar 12;33(3):355-367.e7. https://doi.org/10.1016/j.ccell.2018.02.004
Morita, Mami ; Sato, Taku ; Nomura, Miyuki ; Sakamoto, Yoshimi ; Inoue, Yui ; Tanaka, Ryota ; Ito, Shigemi ; Kurosawa, Koreyuki ; Yamaguchi, Kazunori ; Sugiura, Yuki ; Takizaki, Hiroshi ; Yamashita, Yoji ; Katakura, Ryuichi ; Sato, Ikuro ; Kawai, Masaaki ; Okada, Yoshinori ; Watanabe, Hitomi ; Kondoh, Gen ; Matsumoto, Shoko ; Kishimoto, Ayako ; Obata, Miki ; Matsumoto, Masaki ; Fukuhara, Tatsuro ; Motohashi, Hozumi ; Suematsu, Makoto ; Komatsu, Masaaki ; Nakayama, Keiichi I. ; Watanabe, Toshio ; Soga, Tomoyoshi ; Shima, Hiroshi ; Maemondo, Makoto ; Tanuma, Nobuhiro. / PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth. In: Cancer Cell. 2018 ; Vol. 33, No. 3. pp. 355-367.e7.
@article{825be98a8fa54b5caf2482f98bf8180a,
title = "PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth",
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 KRASG12D-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. The relative importance of PKM isoforms in tumor growth has been controversial. Morita et al. show that PKM1 promotes the growth of multiple tumor models using mouse lines expressing PKM1 or PKM2 from the endogenous Pkm locus. PKM1 is expressed in human SCLC, and it is important for SCLC cell proliferation.",
keywords = "autophagy, glucose metabolism, lung neuroendocrine tumor, mitophagy, PKM, PKM1, PKM2, small-cell lung cancer",
author = "Mami Morita and Taku Sato and Miyuki Nomura and Yoshimi Sakamoto and Yui Inoue and Ryota Tanaka and Shigemi Ito and Koreyuki Kurosawa and Kazunori Yamaguchi and Yuki Sugiura and Hiroshi Takizaki and Yoji Yamashita and Ryuichi Katakura and Ikuro Sato and Masaaki Kawai and Yoshinori Okada and Hitomi Watanabe and Gen Kondoh and Shoko Matsumoto and Ayako Kishimoto and Miki Obata and Masaki Matsumoto and Tatsuro Fukuhara and Hozumi Motohashi and Makoto Suematsu and Masaaki Komatsu and Nakayama, {Keiichi I.} and Toshio Watanabe and Tomoyoshi Soga and Hiroshi Shima and Makoto Maemondo and Nobuhiro Tanuma",
year = "2018",
month = "3",
day = "12",
doi = "10.1016/j.ccell.2018.02.004",
language = "English",
volume = "33",
pages = "355--367.e7",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth

AU - Morita, Mami

AU - Sato, Taku

AU - Nomura, Miyuki

AU - Sakamoto, Yoshimi

AU - Inoue, Yui

AU - Tanaka, Ryota

AU - Ito, Shigemi

AU - Kurosawa, Koreyuki

AU - Yamaguchi, Kazunori

AU - Sugiura, Yuki

AU - Takizaki, Hiroshi

AU - Yamashita, Yoji

AU - Katakura, Ryuichi

AU - Sato, Ikuro

AU - Kawai, Masaaki

AU - Okada, Yoshinori

AU - Watanabe, Hitomi

AU - Kondoh, Gen

AU - Matsumoto, Shoko

AU - Kishimoto, Ayako

AU - Obata, Miki

AU - Matsumoto, Masaki

AU - Fukuhara, Tatsuro

AU - Motohashi, Hozumi

AU - Suematsu, Makoto

AU - Komatsu, Masaaki

AU - Nakayama, Keiichi I.

AU - Watanabe, Toshio

AU - Soga, Tomoyoshi

AU - Shima, Hiroshi

AU - Maemondo, Makoto

AU - Tanuma, Nobuhiro

PY - 2018/3/12

Y1 - 2018/3/12

N2 - 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 KRASG12D-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. The relative importance of PKM isoforms in tumor growth has been controversial. Morita et al. show that PKM1 promotes the growth of multiple tumor models using mouse lines expressing PKM1 or PKM2 from the endogenous Pkm locus. PKM1 is expressed in human SCLC, and it is important for SCLC cell proliferation.

AB - 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 KRASG12D-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. The relative importance of PKM isoforms in tumor growth has been controversial. Morita et al. show that PKM1 promotes the growth of multiple tumor models using mouse lines expressing PKM1 or PKM2 from the endogenous Pkm locus. PKM1 is expressed in human SCLC, and it is important for SCLC cell proliferation.

KW - autophagy

KW - glucose metabolism

KW - lung neuroendocrine tumor

KW - mitophagy

KW - PKM

KW - PKM1

KW - PKM2

KW - small-cell lung cancer

UR - http://www.scopus.com/inward/record.url?scp=85042821230&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042821230&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2018.02.004

DO - 10.1016/j.ccell.2018.02.004

M3 - Article

C2 - 29533781

AN - SCOPUS:85042821230

VL - 33

SP - 355-367.e7

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 3

ER -